BR112017020015B1 - MOLECULES HAVING PESTICIDE UTILITY, ITS INTERMEDIATES, COMPOSITION, AND PROCESS TO CONTROL A PEST - Google Patents

MOLECULES HAVING PESTICIDE UTILITY, ITS INTERMEDIATES, COMPOSITION, AND PROCESS TO CONTROL A PEST Download PDF

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Publication number
BR112017020015B1
BR112017020015B1 BR112017020015-5A BR112017020015A BR112017020015B1 BR 112017020015 B1 BR112017020015 B1 BR 112017020015B1 BR 112017020015 A BR112017020015 A BR 112017020015A BR 112017020015 B1 BR112017020015 B1 BR 112017020015B1
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Brazil
Prior art keywords
dichloro
trans
isolated
chloro
spp
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BR112017020015-5A
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Portuguese (pt)
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BR112017020015B8 (en
BR112017020015A2 (en
Inventor
Joseph D. Eckelbarger
Daniel I. Knueppel
Ronald J. Heemstra
Ronald Ross
Kyle A. Dekorver
Kaitlyn Gary
Peter Vednor
Timothy P. Martin
Ricky Hunter
David A. Demeter
Tony K. Trullinger
Erich W. Baum
Zoltan L. Benko
Nakyen Choy
Gary D. Crouse
John F. Daeuble
Fangzheng Li
Jeffrey NISSEN
Michelle Riener
Thomas C. Sparks
Frank J. Wessels
Maurice C. Yap
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Dow Agrosciences Llc
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Publication of BR112017020015A2 publication Critical patent/BR112017020015A2/en
Publication of BR112017020015B1 publication Critical patent/BR112017020015B1/en
Publication of BR112017020015B8 publication Critical patent/BR112017020015B8/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof
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    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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Abstract

esta descrição refere-se ao campo de moléculas que têm utilidade pesticida contra pragas nos filos arthropoda, mollusca e nematoda, processos para produzir essas moléculas, intermediários usados nesses processos, composições pesticidas contendo essas moléculas, e processos de uso dessas composições pesticidas contra tais pragas. essas composições pesticidas podem ser usadas, por exemplo, como acaricidas, inseticidas, miticidas, moluscicidas e nematicidas. este documento divulga moléculas com a seguinte fórmula ("fórmula um").this description refers to the field of molecules that have pesticidal utility against pests in the arthropoda, mollusca and nematoda phyla, processes for producing these molecules, intermediates used in these processes, pesticidal compositions containing these molecules, and processes for using these pesticidal compositions against such pests . such pesticidal compositions can be used, for example, as acaricides, insecticides, miticides, molluscicides and nematicides. this document discloses molecules with the following formula ("formula one").

Description

Referências Cruzadas a Pedidos RelacionadosCross References to Related Orders

[0001] Este pedido reivindica o benefício e prioridade dos pedidos provisórios números de série US 62/148,830; US 62/148,837; US 62/148,809; US 62/148,814; US 62/148,818; e US 62/148,824; todos os quais foram depositados em 17 de abril de 2015. O teor de todos os pedidos identificados acima é incorporado por referência por meio deste documento neste pedido.[0001] This order claims the benefit and priority of provisional orders US serial numbers 62/148,830; US 62/148,837; US 62/148,809; US 62/148,814; US 62/148.818; and US 62/148,824; all of which were filed on April 17, 2015. The contents of all applications identified above are incorporated by reference herein into this application.

Campo da InvençãoField of Invention

[0002] A presente invenção se refere ao campo de moléculas com utilidade pesticida contra pragas dos Filos Arthropoda, Mollusca e Ne- matoda, processos para produzir tais moléculas, intermediários usados em tais processos, composições pesticidas contendo tais moléculas, e processos de uso de tais composições pesticidas contra tais pragas. Essas composições pesticidas podem ser usadas, por exemplo, como acaricidas, inseticidas, miticidas, moluscicidas e nematicidas.[0002] The present invention refers to the field of molecules with pesticidal utility against pests of the Phylum Arthropoda, Mollusca and Nematoda, processes to produce such molecules, intermediates used in such processes, pesticide compositions containing such molecules, and processes of use of such pesticide compositions against such pests. Such pesticidal compositions can be used, for example, as acaricides, insecticides, miticides, molluscicides and nematicides.

Antecedentes da InvençãoBackground of the Invention

[0003] "Muitas das doenças humanas mais perigosas são transmitidas por vetores insetos" (Rivero et al.). "Historicamente, malária, dengue, febre amarela, peste, filariose, tifo transmitido por piolhos, tri- panossomíase, leishmaniose e outras doenças transmitidas por vetores foram responsáveis por mais doenças humanas e morte no século 17o até o início do século 20o do que todas as outras causas combinadas" (Gubler). Doenças transmitidas por vetores são responsáveis por cerca de 17% das doenças parasíticas e infecciosas no mundo. A malária por si só causa mais de 800.000 mortes por ano, 85% das quais ocorrem em crianças abaixo de cinco anos de idade. Todos os anos há cerca de 50 a cerca de 100 milhões de casos de dengue. 250.000 a 500.000 casos adicionais de dengue hemorrágica ocorrem todos os anos (Matthews). O controle vetorial desempenha um papel crítico na prevenção e controle de doenças infecciosas. No entanto, resistência a inseticidas, incluindo resistência a múltiplos inseticidas, surgiu em todas as espécies de insetos que são os principais vetores de doenças humanas (Rivero et al.). Recentemente, mais de 550 espécies de artrópodes desenvolveram resistência a pelo menos um pesticida (Wha- lon et al.). Além disso, os casos de resistência de insetos continuam a exceder em demasia o número de casos de resistência a herbicidas e fungicidas (Sparks et al.).[0003] "Many of the most dangerous human diseases are transmitted by insect vectors" (Rivero et al.). "Historically, malaria, dengue, yellow fever, plague, filariasis, lice-borne typhus, trypanosomiasis, leishmaniasis, and other vector-borne diseases accounted for more human disease and death in the 17th to the early 20th century than all the other causes combined" (Gubler). Vector-borne diseases are responsible for about 17% of parasitic and infectious diseases in the world. Malaria alone causes more than 800,000 deaths a year, 85% of which occur in children under the age of five. Every year there are about 50 to about 100 million cases of dengue. 250,000 to 500,000 additional cases of dengue hemorrhagic fever occur each year (Matthews). Vector control plays a critical role in the prevention and control of infectious diseases. However, insecticide resistance, including resistance to multiple insecticides, has emerged in all insect species that are major vectors of human disease (Rivero et al.). More than 550 species of arthropods have recently developed resistance to at least one pesticide (Whalon et al.). Furthermore, cases of insect resistance continue to far exceed the number of cases of resistance to herbicides and fungicides (Sparks et al.).

[0004] Todos os anos, insetos, patógenos de plantas e ervas daninha destroem mais de 40% de toda a produção de alimentos. Essa perda ocorre apesar da aplicação de pesticidas e do uso de uma ampla variedade de controles não químicos, tais como rotações de cultura e controles biológicos. Se somente parte desse alimento pudesse ser conservada, poderia ser usada para alimentar mais de três bilhões de pessoas no mundo que estão desnutridas (Pimental).[0004] Every year, insects, plant pathogens and weeds destroy more than 40% of all food production. This loss occurs despite the application of pesticides and the use of a wide variety of non-chemical controls, such as crop rotations and biological controls. If only part of this food could be conserved, it could be used to feed more than three billion people in the world who are malnourished (Pimental).

[0005] Nematódeos parasitas de plantas estão entre as pragas mais difundidas e são frequentemente uma das mais insidiosas e onerosas. Estimou-se que perdas atribuíveis a nematódeos vão de cerca de 9% em países desenvolvidos a cerca de 15% em países subdesenvolvidos. No entanto, nos Estados Unidos da América uma pesquisa em 35 estados em várias culturas indicou perdas causadas por nema- tódeos de até 25% (Nicol et al.).[0005] Plant parasitic nematodes are among the most widespread pests and are often one of the most insidious and costly. It has been estimated that losses attributable to nematodes range from around 9% in developed countries to around 15% in underdeveloped countries. However, in the United States of America a survey of 35 states in various cultures indicated losses caused by nematodes of up to 25% (Nicol et al.).

[0006] Nota-se que gastrópodes (lesmas e caracóis) são pragas de menor importância econômica do que outros artrópodes ou nema- tódeos, mas em certos lugares podem reduzir as colheitas substancialmente, afetando gravemente a qualidade de produtos colhidos, bem como transmitindo doenças ao ser humano, a animais e plantas. Em- bora somente algumas dúzias de espécies de gastrópodes sejam pragas regionais graves, algumas espécies são pragas importantes em escala mundial. Particularmente, gastrópodes afetam uma ampla variedade de culturas agrícolas e hortícolas, tais como culturas aráveis, pastorais e de fibras; legumes; arbustos e árvores frutíferas; ervas; e plantas ornamentais (Speiser).[0006] It is noted that gastropods (slugs and snails) are pests of less economic importance than other arthropods or nematodes, but in certain places they can reduce harvests substantially, severely affecting the quality of harvested products, as well as transmitting diseases to humans, animals and plants. While only a few dozen species of gastropods are serious regional pests, some species are major pests on a world scale. In particular, gastropods affect a wide variety of agricultural and horticultural crops, such as arable, pastoral and fiber crops; vegetables; shrubs and fruit trees; herbs; and ornamental plants (Speiser).

[0007] Cupins causam danos a todos os tipos de estruturas públicas e privadas, bem como a recursos agrícolas e florestais. Em 2005, estimava-se que cupins causassem mais de US$50 bilhões em danos em todo o mundo todos os anos (Korb).[0007] Termites cause damage to all types of public and private structures, as well as agricultural and forest resources. In 2005, termites were estimated to cause more than $50 billion in damage worldwide each year (Korb).

[0008] Consequentemente, por muitas razões, incluindo aquelas mencionadas acima, há uma necessidade constante do desenvolvimento oneroso (cerca de US$256 milhões por pesticida em 2010), demorado (em média cerca de 10 anos por pesticida) e difícil de novos pesticidas (CropLife América).Certas referências citadas nesta divulgaçãoCropLife America, The Cost of New Agrochemical Product Discovery, Development & Registration, and Research & Development predictions for the Future, 2010.Drewes, M., Tietjen, K., Sparks, T.C., High-Throughput Screening in Agrochemical Research, Modern Methods in Crop Protection Research, Parte I, Methods for the Design and Optimization of New Active Ingredients, Editado por Jeschke, P., Kramer, W., Schirmer, U., e Matthias W., p. 1-20, 2012.Gubler, D., Resurgent Vector-Borne Diseases as a Global Health Problem, Emerging Infectious Diseases, Vol. 4, No. 3, p. 442-450, 1998.Korb, J., Termites, Current Biology, Vol. 17, No. 23, 2007.Matthews, G., Integrated Vector Management: Controlling Vectors of Malaria and Other Insect Vector Borne Diseases, C. 1, p. 1, 2011. Nicol, J., Turner S., Coyne, L., den Nijs, L., Hocksland, L., Tahna-Maafi, Z., Current Nematode Threats to World Agriculture, Genomic and Molecular Genetics of Plant - Nematode Interactions, p. 21-43, 2011.Pimental, D., Pest Control in World Agriculture, Agricultural Sciences - Vol. II, 2009.Rivero, A., Vezilier, J., Weill, M., Read, A., Gandon, S., Insect Control of Vector-Borne Diseases: When é Insect Resistance a Problem? Public Library of Science Pathogens, Vol. 6, No. 8, p. 1-9, 2010.Sparks T.C., Nauen R., IRAC: Mode of action classification and insecticide resistance management, Pesticide Biochemistry and Physiology (2014) disponível online em 4 de dezembro de 2014.Speiser, B., Molluscicides, Encyclopedia of Pest Management, C. 219, p. 506-508, 2002.Whalon, M., Mota-Sanchez, D., Hollingworth, R., Analysis of Global Pesticide Resistance in Arthropods, Global Pesticide Resistance in Arthropods, C. 1, p. 5-33, 2008.[0008] Consequently, for many reasons, including those mentioned above, there is a constant need for costly (about US$256 million per pesticide in 2010), time-consuming (on average about 10 years per pesticide) and difficult development of new pesticides ( CropLife America). Certain references cited in this disclosure CropLife America, The Cost of New Agrochemical Product Discovery, Development & Registration, and Research & Development predictions for the Future, 2010. Drewes, M., Tietjen, K., Sparks, TC, High- Throughput Screening in Agrochemical Research, Modern Methods in Crop Protection Research, Part I, Methods for the Design and Optimization of New Active Ingredients, Edited by Jeschke, P., Kramer, W., Schirmer, U., and Matthias W., p. . 1-20, 2012. Gubler, D., Resurgent Vector-Borne Diseases as a Global Health Problem, Emerging Infectious Diseases, Vol. 4, No. 3, p. 442-450, 1998. Korb, J., Termites, Current Biology, Vol. 17, No. 23, 2007. Matthews, G., Integrated Vector Management: Controlling Vectors of Malaria and Other Insect Vector Borne Diseases, C. 1, for. 1, 2011. Nicol, J., Turner S., Coyne, L., den Nijs, L., Hocksland, L., Tahna-Maafi, Z., Current Nematode Threats to World Agriculture, Genomic and Molecular Genetics of Plant - Nematode Interactions, p. 21-43, 2011. Pimental, D., Pest Control in World Agriculture, Agricultural Sciences - Vol. II, 2009. Rivero, A., Vezilier, J., Weill, M., Read, A., Gandon, S. , Insect Control of Vector-Borne Diseases: When is Insect Resistance a Problem? Public Library of Science Pathogens, Vol. 6, No. 8, p. 1-9, 2010. Sparks TC, Nauen R., IRAC: Mode of action classification and insecticide resistance management, Pesticide Biochemistry and Physiology (2014) available online December 4, 2014. Speiser, B., Molluscicides, Encyclopedia of Pest Management, C. 219, p. 506-508, 2002. Whalon, M., Mota-Sanchez, D., Hollingworth, R., Analysis of Global Pesticide Resistance in Arthropods, Global Pesticide Resistance in Arthropods, C. 1, p. 5-33, 2008.

Definições usadas nesta InvençãoDefinitions used in this Invention

[0009] Os exemplos dados nestas definições são geralmente não exaustivos e não devem ser interpretados como limitantes desta divulgação. Entende-se que um substituinte deve cumprir com as regras de ligações químicas e restrições de compatibilidade estérica em relação à molécula em particular à qual ele está ligado. Essas definições devem ser usadas somente para os fins desta divulgação.[0009] The examples given in these definitions are generally non-exhaustive and should not be construed as limiting this disclosure. It is understood that a substituent must comply with the rules of chemical bonding and steric compatibility restrictions with respect to the particular molecule to which it is attached. These definitions are to be used only for the purposes of this disclosure.

[00010] A frase "princípio ativo" significa um material com atividade útil no controle de pragas, e/ou que seja útil no auxílio de outros materiais a ter melhor atividade no controle de pragas, exemplos de tais materiais incluem, mas não estão limitados a, acaricidas, algicidas, produtos com efeito antialimentar, avicidas, bactericidas, repelentes de aves, quimioesterilizantes, fungicidas, fitoprotetores contra herbicidas, herbicidas, atrativos de insetos, repelentes de insetos, inseticidas, repelentes de mamíferos, disruptores de acasalamento, moluscicidas, nematicidas, ativadores de plantas, reguladores do crescimento vegetal, rodenticidas, sinergistas e virucidas (vide alanwood.net). Exemplos específicos de tais materiais incluem, mas não estão limitados a, materiais listados no grupo de princípios ativos alfa.[00010] The phrase "active ingredient" means a material with useful activity in pest control, and/or which is useful in helping other materials to have better activity in pest control, examples of such materials include, but are not limited to a, acaricides, algaecides, products with anti-food effect, avicides, bactericides, bird repellents, chemosterilizers, fungicides, phytoprotectants against herbicides, herbicides, insect attractants, insect repellents, insecticides, mammal repellents, mating disruptors, molluscicides, nematicides , plant activators, plant growth regulators, rodenticides, synergists and virucides (see alanwood.net). Specific examples of such materials include, but are not limited to, materials listed in the alpha group of active ingredients.

[00011] A frase "grupo de princípios ativos alfa" (doravante "AI- GA") significa coletivamente os seguintes materiais:(1) brometo de (3-etoxipropil)mercúrio, 1,2-dibromoe- tano, 1,2-dicloroetano, 1,2-dicloropropano, 1,3-dicloropropeno, 1- MCP, 1-metilciclopropeno, 1-naftol, 2-(octiltio)etanol, 2,3,3-TPA, ácido 2,3,5-tri-iodobenzoico, 2,3,6-TBA, 2,4,5-T, 2,4,5-TB, 2,4,5-TP, 2,4-D, 2,4-DB, 2,4-DEB, 2,4-DEP, 2,4-DES, 2,4-DP, 2,4-MCPA, 2,4-MCPB, 2iP, cloreto de 2-metoxietilmercúrio, 2-fenilfenol, 3,4-DA, 3,4-DB, 3,4-DP, ácido 3,6-dicloropicolínico, 4-aminopiridina, 4-CPA, 4-CPB, 4-CPP, álcool 4-hidroxifenetílico, sulfato de 8-hidroxiqui- nolina, 8-fenilmercurioxiquinolina, abamectin, abamectin-aminometila, ácido abscísico, ACC, acefato, acequinocila, acetamiprida, acetion, acetoclor, acetofenato, acetofos, acetoprol, acibenzolar, acifluorfeno, aclonifeno, ACN, acrep, acrinatrina, acroleína, acrilonitrila, acipetacs, afidopiropeno, afoxolaner, alaclor, alanap, alanicarb, albendazol, aldicarb, aldicarb sulfona, aldimorf, aldoxicarb, aldrin, aletrin, alicin, alido- clor, alosamidina, aloxidim, álcool alílico, alixicarb, alorac, alfa-ciper- metrina, alfa-endosulfan, alfametrina, altretamina, fosfeto de alumínio, fosfeto de alumínio, ametoctradina, ametridiona, ametrin, ametrina, amibuzin, amicarbazona, amicartiazol, amidition, amidoflumet, amido- sulfuron, aminocarb, aminociclopiraclor, aminopiralida, aminotriazol, amiprofos-metila, amiprofos, amiprofos-metila, amisulbrom, amiton, amitraz, amitrol, sulfamato de amônio, amobam, gel de sílica amorfa, dióxido de silício amorfo, ampropilfos, AMS, anabasina, ancimidol, ani- lazina, anilofos, anisuron, antraquinona, antu, afolato, aramita, arpro- carb, óxido arsenoso, asomato, aspirina, asulam, atidation, atraton, atrazina, aureofungina, avermectin B1, AVG, aviglicina, azaconazol, azadiractin, azafenidina, azametifos, azidition, azimsulfuron, azinfosetila, azinfos-etila, azinfosmetila, azinfos-metila, aziprotrin, aziprotrina, aziti- ram, azobenzeno, azocicloestanho, azotoato, azoxistrobina, bachme- desh, barban, barbanato, hexafluorosilicato de bário, polissulfeto de bário, silicofluoreto de bário, bartrin, carbonato de cobre básico, cloreto de cobre básico, sulfato de cobre básico, BCPC, beflubutamid, benala- xila, benalaxil-M, benazolin, bencarbazona, benclotiaz, bendaqingbin- gzhi, bendiocarb, bendióxido, benefin, benfluralin, benfuracarb, benfu- resato, benmihuangcaoan, benodanila, benomila, benoxacor, benoxa- fos, benquinox, bensulfuron, bensulida, bensultap, bentaluron, benta- zon, bentazona, bentiavalicarb, bentiazol, bentiocarb, bentranila, benzadox, cloreto de benzalcônio, benzamacrila, benzamizol, benzamorf, hexacloreto de benzeno, benzfendizona, benzimina, benzipram, ben- zobiciclon, benzoepin, benzofenap, benzofluor, ácido benzohidroxâmi- co, benzomato, benzofosfato, benzotiadiazol, benzovindiflupir, ben- zoximato, benzoilprop, benztiazuron, benzuocaotong, benzoato de benzila, benziladenina, berberina, beta-ciflutrin, beta-cipermetrin, betoxazin, BHC, bialafos, biciclopirona, bifenazato, bifenox, bifentrin, bifu- junzhi, bilanafos, binapacrila, bingqingxiao, bioalletrin, bioetanometrin, biopermetrin, bioresmetrin, bifenila, bisazir, bismertiazol, bismertiazol- cobre, metilenodi(x-naftaleno-i-sulfonato) de bisfenilmercúrio, bispiri- bac, bistrifluron, bisultap, bitertanol, bitionol, bixafen, blasticidin-S, borax, mistura Bordeaux, ácido bórico, boscalid, BPPS, brassinolida, brassinolida-etila, brevicomin, brodifacoum, brofenprox, brofenvalera- to, broflanilida, broflutrinato, bromacila, bromadiolona, bromclofos, brometalin, brometrin, bromfenvinfos, bromoacetamida, bromobonila, bromobutida, bromociclen, bromocicleno, bromo-DDT, bromofenoxim, bromofos, bromometano, bromofos, bromofos-etila, bromopropilato, bromotalonila, bromoxinila, brompirazon, bromuconazol, bronopol, BRP, BTH, bucarpolato, bufencarb, buminafos, bupirimato, buprofezin, mistura Burgundy, busulfan, busulfano, butacarb, butaclor, butafenaci- la, butam, butamifos, butano-fipronila, butatiofos, butenaclor, buteno- fipronila, butetrin, butidazol, butiobato, butiuron, butifos, butocarboxim, butonato, butopironoxila, butoxicarboxim, butralin, butrizol, butroxidim, buturon, butilamina, butilato, butilclorofos, butileno-fipronila, ácido ca- codílico, cadusafos, cafenstrol, calciferol, arsenato de cálcio, clorato de cálcio, cianamida cálcica, cianida cálcica, polissulfeto de cálcio, calvin- fos, cambendihlor, camfeclor, cânfora, captafol, captan, carbam, car- bamorf, carbanolato, carbarila, carbarila, carbasulam, carbation, carbendazim, carbendazol, carbetamida, carbofenotion, carbofuran, dis- sulfeto de carbono, tetracloreto de carbono, sulfeto de carbonila, car- bofenotion, carbofos, carbosulfan, carboxazol, carboxida, carboxin, carfentrazona, carpropamid, cartap, carvacrol, carvona, CAVP, CDAA, CDEA, CDEC, cellocidin, CEPC, ceralure, cerenox, cevadilla, mistura Cheshunt, quinalfos, quinalfos-metila, quinometionat, quinometionato, quiralaxila, quitosana, clobentiazona, clometoxifeno, cloralose, cloram- ben, cloramina fosforosa, cloramfenicol, cloraniformetan, cloranila, clo- ranocrila, clorantraniliprol, clorazifop, clorazina, clorbensida, clorbenzu- ron, clorbiciclen, clorbromuron, clorbufam, clordano, clordecona, clor- dimeform, clorempentrin, cloretazato, cloretefon, cloretoxifos, cloretu- ron, clorfenac, clorfenapir, clorfenazol, clorfenetol, clorfenidim, clorfen- prop, clorfenson, clorfensulfeto, clorfenvinfos, clorfenvinfos-metila, clorfluazuron, clorflurazol, clorflurecol, clorfluren, clorflurenol, clorida- zon, clorimuron, clorinato, clor-IPC, clormefos, clormequat, clormesu- lona, clormetoxinila, clornidina, clornitrofen, ácido cloroacético, cloro- benzilato, clorodinitronaftalenos, clorofenizon, clorofórmio, cloromebu- form, clorometiuron, cloroneb, clorofacinona, clorofos, cloropicrin, clo- ropon, cloropropilato, clorotalonila, clorotoluron, cloroxifenidim, cloroxu- ron, cloroxinila, clorfônio, clorfoxim, clorprazofos, clorprocarb, clorpro- fam, clorpirifos, clorpirifos-metila, clorquinox, clorsulfuron, clortal, clor- tiamid, clortiofós, clortoluron, clozolinato, quitosana, colecalciferol, cloreto de colina, cromafenozida, ciclo-heximida, cimectacarb, cimeta- carb, cinerin I, cinerin II, cinerins, cinidon-etila, cinmetilina, cinosulfu- ron, cintofen, ciobutida, cisanilida, cismetrin, clacifos, clefoxidim, clen- pirin, clenpirina, cletodim, climbazol, cliodinato, clodinafop, cloetocarb, clofencet, clofenotano, clofentezina, clofenvinfos, ácido clofíbrico, clofop, clomazona, clomeprop, clonitralid, cloprop, cloproxidim, clopira- lid, cloquintocet, cloransulam, closantel, clotianidin, clotrimazol, cloxi- fonac, cloxilacon, clozilacon, CMA, CMMP, CMP, CMU, codlelure, colecalciferol, colofonato, 8-quinolinolato de cobre, acetato de cobre, acetoarsenito de cobre, arsenato de cobre, carbonato de cobre básico, hidróxido de cobre, naftenato de cobre, oleato de cobre, oxicloreto de cobre, silicato de cobre, sulfato de cobre, sulfato de cobre básico, cro- mato de cobre e zinco, coumaclor, coumafeno, coumafos, coumafurila, coumafos, coumatetralila, coumetoxistrobin, coumitoato, coumoxistro- bin, CPMC, CPMF, CPPC, credazine, cresol, ácido cresílico, crimidina, crotamiton, crotoxifos, crotoxifos, crufomato, criolita, cue-lure, cufra- neb, cumileron, cumiluron, cuprobam, óxido cuproso, curcumenol, CVMP, cianamida, cianatrin, cianazina, caanofenfos, cianogen, ciano- fos, ciantoato, ciantraniliprol, ácido cianúrico, ciazofamid, cibutrina, ci- clafuramid, ciclanilida, ciclaniliprol, cicletrin, cicloato, ciclo-heximida, cicloprato, cicloprotrin, ciclopirimorato, ciclosulfamuron, cicloxidim, ci- cluron, cienopirafen, ciflufenamid, ciflumetofen, ciflutrin, cihalofop, ciha- lotrin, ci-hexaestanho, cimiazol, cimoxanila, ciometrinila, cipendazol, cipermetrin, ciperquat, cifenotrin, ciprazina, ciprazol, ciproconazol, ci- prodinila, ciprofuram, cipromid, ciprosulfamida, ciromazina, citioato, citrex, daimuron, dalapon, daminozida, dayoutong, dazomet, DBCP, d- cânfora, DCB, DCIP, DCPA, DCPTA, DCU, DDD, DDPP, DDT, DDVP, debacarb, decafentin, decametrin, decarbofuran, deet, ácido desidroa- cético, deiquat, delaclor, delnav, deltametrin, demefion, demefion-O, demefion-S, demeton, demeton-metila, demeton-O, demeton-O- metila, demeton-S, demeton-S-metila, demeton-S-metil sulfona, de- meton-S-metilsulfona, DEP, depallétrina, derris, desmedifam, desme- trin, desmetrina, d-fanshiluquebingjuzhi, diafentiuron, dialifor, dialifos, diallato, diamidafos, dianat, terra diatomácea, diatomita, diazinon, dibrom, ftalato de dibutila, succinato de dibutila, dicamba, dicapton, di- clobenila, diclofention, diclofluanid, diclona, dicloralureia, diclorbenzu- ron, diclorfenidim, diclorflurecol, diclorflurenol, diclormato, diclormid, diclorometano, dicloromezotiaz, diclorofeno, diclorprop, diclorprop-P, diclorvos, diclozolin, diclozolina, diclobutrazol, diclocimet, diclofop, di- clomezina, dicloran, diclosulam, dicofol, dicofano, dicoumarol, dicresila, dicrotofos, dicrila, dicumarol, diciclanila, diciclonon, dieldrin, dienoclor, dietamquat, dietatila, dietion, diétion, dietofencarb, dietolato, diéton, pirocarbonato de dietila, dietiltoluamida, difenacoum, difenoconazol, difenopenten, difenoxuron, difenzoquat, difetialona, diflovidazin, diflu- benzuron, diflufenican, diflufenicanila, diflufenzopir, diflumetorim, dike- gulac, dilor, dimatif, dimeflutrin, dimefox, dimefuron, dimehipo, dimepi- perato, dimetaclona, dimetan, dimetacarb, dimetaclona, dimetaclor, dimetametrin, dimetenamid, dimetenamid-P, dimetipin, dimetirimol, dimetoato, dimetomorf, dimetrin, carbato de dimetila, dissulfeto de di- metila, ftalato de dimetila, dimetilvinfos, dimetilan, dimexano, dimida- zon, dimoxistrobin, dimpilato, dimuron, dinex, dingjunezuo, diniconazol, diniconazol-M, dinitramina, dinitrofenóis, dinobuton, dinocap, dinocap- 4, dinocap-6, dinocton, dinofenato, dinopenton, dinoprop, dinosam, dinoseb, dinosulfon, dinotefuran, dinoterb, dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxation, dioxation, difacin, difacinona, di- fenadiona, difenamid, difenamida, difenil sulfona, difenilamina, dife- nilsulfeto, ácido diprogúlico, dipropalin, dipropetrin, dipterex, dipimeti- trona, dipiritiona, diquat, tetraborato dissódico, disosultap, disparlure, disugran, disul, disulfiram, disulfoton, ditalimfos, ditianon, diticrofos, ditioéter, ditiométon, ditiopir, diuron, dixantogen, d-limoneno, DMDS, DMPA, DNOC, dodemorf, dodicin, dodina, dofenapin, doguadina, do- minicalure, doramectin, DPC, drazoxolon, DSMA, d-trans-alletrin, d- trans-resmetrin, dufulin, dimron, EBEP, EBP, ebufos, ecdisterona, eclomezol, EDB, EDC, EDDP, edifenfos, eglinazina, emamectin, EMPC, empentrin, enadenina, endosulfan, endotal, endotall, endotion, endrin, enestroburin, enilconazol, enoxastrobin, efirsulfonato, EPN, epocoleona, epofenonano, epoxiconazol, eprinomectin, epronaz, EPTC, erbon, ergocalciferol, erlujixiancaoan, esdépallétrina, esfenvale- rato, ESP, esprocarb, etacelasila, etaconazol, etafos, etem, etaboxam, etaclor, etalfluralin, etametsulfuron, etaproclor, etefon, etidimuron, etio- fencarb, etiolato, etion, etiozin, etiprol, etirimol, etoato-metila, etoben- zanid, etofumesato, etohexadiol, etoprop, etoprofos, etoxifen, etoxi- quin, etoxisulfuron, eticlozato, formato de etila, pirofosfato de etila, eti- lan, etil-DDD, etileno, dibrometo de etileno, dicloreto de etileno, óxido de etileno, etilicin, etilmercúrio 2,3-dihidroxipropil mercaptida, acetato de etilmercúrio, brometo de etilmercúrio, cloreto de etilmercúrio, fosfato de etilmercúrio, etinofen, ETM, etnipromid, etobenzanid, etofenprox, etoxazol, etridiazol, etrimfos, étrimfos, eugenol, EXD, famoxadona, famfur, fenac, fenamidona, fenaminosulf, fenaminstrobin, fenamifos, fenapanila, fenarimol, fenasulam, fenazaflor, fenazaquin, fenbucona- zol, óxido de fenbutatin, fenclorazol, fenclorfos, fenclofos, fenclorim, fenetacarb, fenflutrin, fenfuram, fen-hexamid, fenidin, fenitropan, feni- trotion, fénizon, fenjuntong, fenobucarb, fenolovo, fenoprop, fenotio- carb, fenoxacrim, fenoxanila, fenoxaprop, fenoxaprop-P, fenoxassulfo- na, fenoxicarb, fenpiclonila, fenpiritrin, fenpropatrin, fenpropidin, fen- propimorf, fenpirazamina, fenpiroximato, fenquinotriona, fenridazon, fenson, fensulfotion, fenteracol, fentiaprop, fention, fention-etila, fenti- aprop, fentin, fentrazamida, fentrifanila, fenuron, fenuron-TCA, fenva- lerato, ferbam, ferimzona, fosfato férrico, sulfato ferroso, fipronila, flamprop, flamprop-M, flazasulfuron, flocoumafen, flometoquin, floni- camid, florasulam, fluacripirim, fluazifop, fluazifop-P, fluazinam, fluazo- lato, fluazuron, flubendiamida, flubenzimina, flubrocitrinato, flucarbazo- na, flucetosulfuron, flucloralin, flucofuron, flucicloxuron, flucitrinato, flu- dioxonila, fluénétila, fluenetila, fluensulfona, flufenacet, flufenerim, flu- fenican, flufenoxuron, flufenoxistrobin, flufenprox, flufenpir, flufenzina, flufiprol, flu-hexafon, flumetrin, flumetover, flumetralin, flumetsulam, flumezin, flumiclorac, flumioxazin, flumipropin, flumorf, fluometuron, fluopicolida, fluopiram, fluorbensida, fluoridamid, fluoroacetamida, ácido fluoroacético, fluorocloridona, fluorodifen, fluoroglicofen, fluoroimi- da, fluoromida, fluoromidina, fluoronitrofen, fluoroxipir, fluotiuron, fluo- trimazol, fluoxastrobin, flupoxam, flupropacila, flupropadina, flupropa- nato, flupiradifurona, flupirsulfuron, fluquinconazol, fluralaner, flurazol, flurecol, flurenol, fluridona, flurocloridona, fluromidina, fluroxipir, flur- primidol, flursulamid, flurtamona, flusilazol, flusulfamida, flutenzina, flu- tiacet, flutiamida, flutianila, flutolanila, flutriafol, fluvalinato, fluxapiroxad, fluxofenim, folpel, folpet, fomesafen, fonofos, foramsulfuron, forclorfe- nuron, formaldeído, formetanato, formotion, formparanato, fosamina, fosetila, fosmetilan, fospirato, fostiazato, fostietan, frontalin, ft-haleto, fuberidazol, fucaojing, fucaomi, fujunmanzhi, fulumi, fumarin, funaihe- caoling, fufentioureia, furalano, furalaxila, furametrin, furametpir, furan tebufenozida, furatiocarb, furcarbanila, furconazol, furconazol-cis, fure- trin, furfural, furilazol, furmeciclox, furofanato, furiloxifen, gama-BHC, gama-ci-halotrin, gama-HCH, genit, ácido giberélico, giberelina A3, giberelinas, gliftor, glitor, glicocloralose, glufosinato, glufosinato-P, gli- odin, glioxima, glifosato, glifosina, gossiplure, grandlure, griseofulvin, guanoctina, guazatina, halacrinato, halauxifen, halfenprox, halofenozi- da, halosafen, halosulfuron, haloxidina, haloxifop, haloxifop-P, haloxi- fop-R, HCA, HCB, HCH, hemel, hempa, HEOD, heptaclor, heptaflutrin, heptenofos, heptopargila, herbimicin, herbimicin A, heterofos, hexaclor, hexacloran, hexacloroacetona, hexaclorobenzeno, hexaclorobutadie- no, hexaclorofeno, hexaconazol, hexaflumuron, hexafluoramin, hexa- flurato, hexalure, hexamida, hexazinona, hexiltiofos, hexitiazox, HHDN, holosulf, homobrassinolida, huancaiwo, huanchongjing, huangcaoling, huanjunzuo, hidrametilnon, hidrargafen, cal hidratada, hidrogeno cia- namida, cianeto de hidrogênio, hidropreno, hidróxi-isoxazol, himexazol, hiquincarb, IAA, IBA, IBP, icaridin, imazalila, imazametabenz, imaza- mox, imazapic, imazapir, imazaquin, imazetapir, imazosulfuron, imi- benconazol, imiciafos, imidacloprid, imidaclotiz, iminoctadina, imipro- trin, inabenfida, indanofan, indaziflam, indoxacarb, inezin, terra infusorial, iodobonila, iodocarb, iodofenfos, iodometano, iodosulfuron, iofen- sulfuron, ioxinila, ipazina, IPC, ipconazol, ipfencarbazona, iprobenfos, iprodiona, iprovalicarb, iprimidam, ipsdienol, ipsenol, IPSP, IPX, isami- dofos, isazofos, isobenzan, isocarbamid, isocarbamida, isocarbofos, isocila, isodrin, isofenfos, isofenfos-metila, isofetamid, isolan, isometi- ozin, isonoruron, isopamfos, isopolinato, isoprocarb, isoprocila, isopropalin, isopropazol, isoprotiolano, isoproturon, isopirazam, isopirimol, isotioato, isotianila, isouron, isovalediona, isoxaben, isoxaclortol, iso- xadifen, isoxaflutol, isoxapirifop, isoxation, isuron, ivermectin, ixoxaben, izopamfos, izopamfos, japonilure, japotrins, jasmolin I, jasmolin II, ácido jasmônico, jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jie- caowan, jiecaóxi, jinganmicin A, jodfenfos, hormônio juvenil I, hormônio juvenil II, hormônio juvenil III, kadetrin, kapa-bifentrin, kapa-teflutrin, karbutilato, karetazan, kasugamicin, kejunlin, kelevan, ketospiradox, kieselguhr, kinetin, kinopreno, kiralaxila, kresoxim-metila, kuicaóxi, lactofen, lambda-ci-halotrin, latilure, arsenato de chumbo, lenacila, lepi- mectin, leptofos, lianbenjingzhi, enxofre de calcário, lindano, lineatin, linuron, lirimfos, litlure, looplure, lufenuron, lüxiancaolin, lvdingjunzhi, Ivfumijvzhi, Ivxiancaolin, litidation, M-74, M-81, MAA, fosfeto de magnésio, malation, maldison, hidrazida maleica, malonoben, maltodextrin, MAMA, mancopper, mancozeb, mandestrobin, mandipropamid, maneb, matrina, mazidox, MCC, MCP, MCPA, MCPA-tioetila, MCPB, MCPP, mebenila, mecarbam, mecarbinzid, mecarfon, mecoprop, me- coprop-P, medimeform, medinoterb, medlure, mefenacet, mefenoxam, mefenpir, mefluidida, ácido megatomoico, álcool melissílico, melitoxi- na, MEMC, menazon, MEP, mepanipirim, meperflutrin, mefenato, me- fosfolan, mepiquat, mepronila, meptildinocap, mercaptodimetur, mer- captofos, mercaptofos tiol, mercaptotion, cloreto mercúrico, óxido mer- cúrico, cloreto mercuroso, merfos, óxido de merfos, mesoprazina, me- sosulfuron, mesotriona, mesulfen, mesulfenfos, mesulfen, metacresol, metaflumizona, metalaxila, metalaxil-M, metaldeído, metam, metami- fop, metamitron, metafos, metaxon, metazaclor, metazosulfuron, meta- zoxolon, metconazol, metepa, metflurazon, metabenztiazuron, metacri- fos, metalpropalin, metam, metamidofos, metasulfocarb, metazol, met- furoxam, metibenzuron, metidation, metiobencarb, metiocarb, metiopi- risulfuron, metiotepa, metiozolin, metiuron, metocrotofos, métolcarb, metometon, metomila, metopreno, metoprotrin, metoprotrina, meto- quin-butila, metotrin, metoxiclor, metoxifenozida, metoxifenona, afolato de metila, brometo de metila, eugenol metílico, iodeto de metila, isotio- cianato de metila, paration metílico, metilacetofos, metilclorofórmio, ácido metilditiocarbâmico, metildimron, cloreto de metileno, metil- isofenfos, metilmercaptofos, óxido de metilmercaptofos, metilmercapto- fos tiol, benzoato de metilmercúrio, metilmercúrio diciandiamida, pen- taclorofenóxido de metilmercúrio, metilneodecanamida, metilnitrofos, metiltriazotion, metiozolin, metiram, metiram-zinco, metobenzuron, metobromuron, metoflutrin, metolaclor, metolcarb, metometuron, me- tominostrobin, metosulam, metoxadiazona, metoxuron, metrafenona, metriam, metribuzin, metrifonato, metrifonate, metsulfovax, metsulfu- ron, mevinfos, mexacarbato, miechuwei, mieshuan, miewenjuzhi, mil- bemectin, milbemicin oxima, milneb, mima2nan, mipafox, MIPC, mirex, MNAF, moguchun, molinato, molosultap, momfluorotrin, monalida, mo- nisuron, monoamitraz, ácido monocloroacético, monocrotofos, monoli- nuron, monomehipo, monosulfiram, monosulfuron, monosultap, monuron, monuron-TCA, morfamquat, moroxidina, morfotion, morzid, moxi- dectin, MPMC, MSMA, MTMC, muscalure, miclobutanila, miclozolin, álcool miricílico, N-(etilmercúrio)-p-toluenossulfonanilida, NAA, NAAm, nabam, naftalofos, naled, naftaleno, naftalenoacetamida, anidrido naftáli- co, naftalofos, ácidos naftoxiacéticos, ácidos naftilacéticos, naftilinda- no-1,3-dionas, ácidos naftiloxiacéticos, naproanilida, napropamida, napropamida-M, naptalam, natamicin, NBPOS, nebureia, neburon, nendrin, neonicotina, niclorfos, niclofen, niclosamida, nicobifen, nico- sulfuron, nicotina, sulfato de nicotina, nifluridida, nikkomicins, NIP, nipi- raclofen, nipiralofen, nitenpiram, nitiazina, nitralin, nitrapirin, nitrilacarb, nitrofen, nitrofluorfen, nitrostireno, nitrotal-isopropila, nobormida, nonanol, norbormida, noreia, norflurazon, nornicotina, noruron, novalu- ron, noviflumuron, NPA, nuarimol, nuranona, OCH, éter octaclorodi- propílico, octilinona, o-diclorobenzeno, ofurace, ometoato, o-fenilfenol, orbencarb, orfralure, ortobencarb, orto-diclorobenzeno, ortosulfamu- ron, orictalure, orisastrobin, orizalin, ostol, ostole, ostramona, ovatron, ovex, oxabetrinila, oxadiargila, oxadiazon, oxadixila, oxamato, oxamila, oxapirazon, oxapirazona, oxasulfuron, oxatiapiprolin, oxaziclomefona, oxina-cobre, oxina-Cu, ácido oxolínico, oxpoconazol, oxicarboxin, oxi- demeton-metila, oxideprofos, oxidisulfoton, oxienadenina, oxifluorfen, oximatrina, oxitetraciclina, oxitioquinox, PAC, paclobutrazol, paichong- ding, pallétrina, PAP, para-diclorobenzeno, parafluron, paraquat, para- tion, paration-metila, parinol, verde Paris, PCNB, PCP, PCP-Na, p- diclorobenzeno, PDJ, pebulato, pédinex, pefurazoato, ácido pelargôni- co, penconazol, pencicuron, pendimetalin, penfenato, penflufen, pen- fluron, penoxalin, penoxsulam, pentaclorofenol, laurato de pentacloro- fenila, pentanoclor, pentiopirad, pentmetrin, pentoxazona, perclordeco- na, perfluidona, permetrin, petoxamid, PHC, fenamacrila, fenamacril- etila, fénaminosulf, óxido de fenazina, fénétacarbe, fenisofam, fenkap- ton, fenmedifam, fenmedifam-etila, fenobenzuron, fenotiol, fenotrin, fenpróxido, fentoato, fenilmercuriureia, acetato de fenilmercúrio, cloreto de fenilmercúrio, derivado fenilmercúrico de pirocatecol, nitrato de fe- nilmercúrio, salicilato de fenilmercúrio, forato, fosacetim, fosalona, fos- ametina, fosazetim, fosazetin, foscicloestanho, fosdifen, fosetila, fosfo- lan, fosfolan-metila, fosglicin, fosmet, fosniclor, fosfamida, fosfamidon, fosfina, fosfinotricin, fosfocarb, fósforo, fostin, foxim, foxim-metila, ftali- da, ftalofos, ftaltrin, picarbutrazox, picaridin, picloram, picolinafen, pico- xistrobin, pimaricin, pindona, pinoxaden, piperalin, piperazina, butóxido de piperonila, piperonil cicloneno, piperofos, piproctanli, piproctanila, piprotal, pirimetafos, pirimicarb, piriminila, pirimioxifos, pirimifos-etila, pirimifos-metila, pival, pivaldiona, plifenato, PMA, PMP, polibutenos, policarbamato, policlorcamfeno, polietoxiquinolina, polioxin D, polioxi- nas, polioxorim, politialan, arsenito de potássio, azida potássica, cianato de potássio, etilxantato de potássio, naftenato de potássio, polissul- feto de potássio, tiocianato de potássio, pp‘-DDT, pralletrin, precoceno I, precoceno II, precoceno III, pretilaclor, primidofos, primisulfuron, pro- benazol, procloraz, proclonol, prociazina, procimidona, prodiamina, profenofos, profluazol, profluralin, proflutrin, profoxidim, profurita- amínio, proglinazina, pro-hexadiona, pro-hidrojasmon, promacila, pro- mecarb, prometon, prometrin, prometrina, promurit, pronamida, propa- clor, propafos, propamidina, propamocarb, propanila, propafos, propa- quizafop, propargita, propartrin, propazina, propetamfos, profam, pro- piconazol, propidina, propineb, propisoclor, propoxur, propoxicarbazo- na, propil isome, propirissulfuron, propizamida, proquinazid, prosuler, prosulfalin, prosulfocarb, prosulfuron, protidation, protiocarb, protioco- nazol, protiofos, protoato, protrifenbute, proxan, primidofos, prinaclor, psoralen, psoraleno, pidanon, piflubumida, pimetrozina, piracarbolid, piraclofos, piraclonila, piraclostrobin, piraflufen, pirafluprol, piramat, pi- rametostrobin, piraoxistrobin, pirassulfotol, piraziflumid, pirazolato, pi- razolinato, pirazon, pirazofos, pirazosulfuron, pirazotion, pirazoxifen, piresmetrin, piretrin I, piretrin II, piretrinas, piribambenz-isopropila, piri- bambenz-propila, piribencarb, piribenzoxim, piributicarb, piriclor, pirida- ben, piridafol, piridalila, piridafention, piridafentiona, piridato, piridinitrila, pirifenox, pirifluquinazon, piriftalid, pirimétafos, pirimetanila, pirimicarbe, pirimidifen, piriminobac, piriminostrobin, pirimifos-etila, pirimifos-metila, pirimissulfan, pirimitato, pirinuron, piriofenona, piriprol, piripropanol, piri- proxifen, pirisoxazol, piritiobac, pirolan, piroquilon, piroxassulfona, pirox- sulam, piroxiclor, piroxifur, qincaosuan, qingkuling, quassia, quinacetol, quinalfos, quinalfos-metila, quinazamid, quinclorac, quinconazol, quin- merac, quinoclamina, quinometionato, quinonamid, quinotion, quinoxi- fen, quintiofos, quintozeno, quizalofop, quizalofop-P, quwenzhi, quyingding, rabenzazol, rafoxanida, R-diniconazol, rebemida, reglona, renriduron, rescalure, resmetrin, rodetanila, rodojaponin-III, ribavirin, rimsulfuron, rizazol, R-metalaxila, rodétanila, ronnel, rotenona, riania, sabadilla, saflufenacila, saijunmao, saisentong, salicilanilida, salifluofen, sanguinarina, santonin, S-bioalletrin, schradan, scillirosida, sebutilazina, secbumeton, sedaxano, selamectin, semiamitraz, sesamex, sesamolin, sesone, setoxidim, sevin, shuangjiaancaolin, shuangjianancaolin, S- hidropreno, siduron, sifumijvzhi, siglure, silafluofen, silatrane, sílica aerogel, sílica gel, siltiofam, siltiopham, siltiophan, silvex, simazina, si- meconazol, simeton, simetrin, simetrina, sintofen, S-kinopreno, cal apagada, SMA, S-metopreno, S-metolaclor, arsenito de sódio, azida de sódio, clorato de sódio, cianeto de sódio, fluoreto de sódio, fluoroaceta- to de sódio, hexafluorossilicato de sódio, naftenato de sódio, o- fenilfenóxido de sódio, ortofenilfenóxido de sódio, pentaclorofenato de sódio, pentaclorofenóxido de sódio, polissulfeto de sódio, silicofluoreto de sódio, tetratiocarbonato de sódio, tiocianato de sódio, solan, sofami- da, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, spi- roxamina, stirofos, streptomicina, estricnina, sulcatol, sulcofuron, sulco- triona, sulfallato, sulfentrazona, sulfiram, sulfluramid, sulfodiazol, sulfo- meturon, sulfosato, sulfosulfuron, sulfotep, sulfotepp, sulfoxaflor, sulfóxi- do, sulfoxime, enxofre, ácido sulfúrico, fluoreto de sulfurila, sulglicapin, sulfosato, sulprofos, sultropen, swep, tau-fluvalinato, tavron, tazimcarb, TBTO, TBZ, TCA, TCBA, TCMTB, TCNB, TDE, tebuconazol, tebufeno- zida, tebufenpirad, tebufloquin, tebupirimfos, tebutam, tebutiuron, teclof- talam, tecnazeno, tecoram, tedion, teflubenzuron, teflutrin, tefuriltriona, tembotriona, temefos, temephos, tepa, TEPP, tepraloxidim, teproloxi- dim, teralletrin, terbacila, terbucarb, terbuclor, terbufos, terbumeton, ter- butilazina, terbutol, terbutrin, terbutrina, terraclor, terramicin, terramicina, tetciclacis, tetrachoroetano, tetraclorvinfos, tetraconazol, tetradifon, tetradisul, tetrafluron, tetrametrin, tetrametilflutrin, tetramina, tetranactin, tetraniliprol, tetrapion, tetrasul, sulfato de tálio, sulfato taloso, tenilclor, teta-cipermetrin, tiabendazol, tiacloprid, tiadiazina, tiadifluor, tiameto- xam, tiameturon, tiapronila, tiazafluron, tiazfluron, tiazona, tiazopir, ticro- fos, ticiofen, tidiazimin, tidiazuron, tiencarbazona, tifensulfuron, tifluza- mida, timerosal, timet, tiobencarb, tiocarboxima, tioclorfenfim, tioclorfen- fima, tiocianatodinitrobenzenos, tiociclam, tiodan, tiodiazol-cobre, tiodi- carb, tiofanocarb, tiofanox, tiofluoximato, tiohempa, tiomersal, tiometon, tionazin, tiofanato, tiofanato-etila, tiofanato-metila, tiofos, tioquinox, ti- osemicarbazida, tiosultap, tiotepa, tioxamila, tiram, tiuram, turingiensin, tiabendazol, tiadinila, tiafenacila, tiaojiean, TIBA, tifatol, tiocarbazila, tio- clorim, tioxazafen, tioximid, tirpato, TMTD, tolclofos-metila, tolfenpirad, tolprocarb, tolpiralato, tolifluanid, tolilfluanid, acetato de tolilmercúrio, tomarin, topramezona, toxafeno, TPN, tralkoxidim, tralocitrin, tralome- trin, tralopirila, transflutrin, transpermetrin, tretamina, triacontanol, tria- dimefon, triadimenol, triafamona, triallato, tri-allato, triamifos, triapen- tenol, triarateno, triarimol, triasulfuron, triazamato, triazbutila, triaziflam, triazofos, triazotion, triazóxido, cloreto de cobre tribásico, sulfato de cobre tribásico, tribenuron, tribufos, óxido de tributilestanho, tricamba, triclamida, triclopir, triclorfon, triclormetafos-3, tricloronat, tricloronato, triclorotrinitrobenzenos, triclorfon, triclopi, triclopiricarb, tricresol, trici- clazol, hidróxido de triciclo-hexilestanho, tridemorf, tridifano, trietazina, trifenmorf, trifenofos, trifloxistrobin, trifloxissulfuron, trifludimoxazin, tri- flumezopirim, triflumizol, triflumuron, trifluralin, triflusulfuron, trifop, trifopsima, triforina, tri-hidroxitriazina, trimedlure, trimetacarb, trimeturon, trinexapac, trifenilestanho, tripreno, tripropindan, triptolida, tritac, tritia- lan, triticonazol, tritosulfuron, trunc-call, tuoielin, uniconazol, unicona- zol-P, urbacida, uredepa, valerato, validamicina, validamicina A, valife- nalato, valona, vamidotion, vangard, vaniliprol, vernolato, vinclozolin, vitamina D3, warfarina, xiaochongliulin, xinjunan, xiwojunan, xiwojunzhi, XMC, xilaclor, xilenóis, xililcarb, ximiazol, yishijing, zarilamid, zeatin, zen- gxiaoan, zengxiaolin, zeta-cipermetrin, naftenato de zinco, fosfeto de zinco, tiazol de zinco, tiozol de zinco, triclorofenato de zinco, triclorofenóxido de zinco, zineb, ziram, zolaprofos, zoocoumarin, zoxamida, zuoanjunzhi, zuocaoan, zuojunzhi, zuomihuanglong, α-clorohidrin, α-ecdisona, α- multistriatin, ácidos a-naftalenoacéticos e β-ecdisona;(2) as seguintes moléculas(a) N-(3-cloro-1-(piridin-3-il)-1H-pirazol-4-il)-N-etil- 3-((3,3,3-trifluoropropil)tio)propanamida (doravante "AI-1")

Figure img0001
(b) isobutirato de (3S,6S,7R,8R)-8-benzil-3-(3-((iso- butirilóxi)metóxi)-4-metoxipicolinamido)-6-metil-4,9-dioxo-1,5-dio-xonan-7-ila (doravante "AI-2")
Figure img0002
(3) uma molécula conhecida como Lotilaner que tem a se-guinte estrutura
Figure img0003
(4) as seguintes moléculas na Tabela ATabela A – Estrutura de M# – princípios ativos
Figure img0004
Figure img0005
[00011] The phrase "group of alpha active ingredients" (hereinafter "AI-GA") collectively means the following materials: (1) (3-ethoxypropyl)mercury bromide, 1,2-dibromoethane, 1,2- dichloroethane, 1,2-dichloropropane, 1,3-dichloropropene, 1-MCP, 1-methylcyclopropene, 1-naphthol, 2-(octylthio)ethanol, 2,3,3-TPA, 2,3,5-tri-acid iodobenzoic, 2,3,6-TBA, 2,4,5-T, 2,4,5-TB, 2,4,5-TP, 2,4-D, 2,4-DB, 2,4- DEB, 2,4-DEP, 2,4-DES, 2,4-DP, 2,4-MCPA, 2,4-MCPB, 2iP, 2-methoxyethylmercury chloride, 2-phenylphenol, 3,4-DA, 3,4-DB, 3,4-DP, 3,6-dichloropicolinic acid, 4-aminopyridine, 4-CPA, 4-CPB, 4-CPP, 4-hydroxyphenethyl alcohol, 8-hydroxyquinoline sulfate, 8- phenylmercurioxyquinoline, abamectin, abamectin-aminomethyl, abscisic acid, ACC, acephate, acequinocyl, acetamiprid, acetion, acetochlor, acetofenate, acetophos, acetoprol, acibenzolar, acifluorfen, aclonicre, acronier, acrophyla, apethine , alachlor, alanap, alanicarb, albendazol, aldicar b, aldicarb sulfone, aldimorph, aldoxicarb, aldrin, alethrin, allicin, alidochlor, allosamidine, aloxidim, allyl alcohol, alixicarb, alorac, alpha-cypermethrin, alpha-endosulfan, alphamethrin, altretamine, aluminum phosphide, phosphide aluminum, amethoctradine, ametridione, ametrin, ametrin, amibuzin, amicarbazone, amicarthiazole, amidition, amidoflumet, amidosulfon, aminocarb, aminocyclopyrachlor, aminopyralide, aminotriazole, amiprophos-methyl, amiprophos, amiprophos, amibroa, amibro, amiprophos, amiprophos, amibrom, amis ammonium sulfamate, amobam, amorphous silica gel, amorphous silicon dioxide, ampropylphos, AMS, anabasin, ancimidol, anilazine, anilophos, anisuron, anthraquinone, antu, afolate, aramite, arprocarb, arsenous oxide, asomate, aspirin , asulam, atidation, atraton, atrazine, aureofungin, avermectin B1, AVG, aviglycin, azaconazole, azadiractin, azafenidin, azamethiphos, azidition, azimsulfuron, azinphosetyl, azinphos-ethyl, azinfospromethyl, azimphostrin, azinfostrin take, azobenzene, azocyclotin, nitrogenate, azoxystrobin, bachmedesh, barban, barbanate, barium hexafluorosilicate, barium polysulfide, barium silicofluoride, barthrin, basic copper carbonate, basic copper chloride, basic copper sulfate, BCPC , beflubutamid, benal-xyl, benalaxyl-M, benazolin, bencarbazone, benclothiaz, bendaqingbingzhi, bendiocarb, bendioxide, benefin, benfluralin, benfuracarb, benfu-resate, benmihuangcaoan, benmihuangcaoan, ben- iladanil, ben- oxan, benox-, ,bensulide,bensultap,bentaluron,bentazon,bentazone,bentiavalicarb,benthiazole,benthiocarb,benthranil,benzadox,benzalkonium chloride, benzamacril, benzamizole, benzamorph, benzene hexachloride, benzfendizone, benzophenzop-en, benzoappine, benzadox , benzofluor, benzohydroxamic acid, benzomate, benzophosphate, benzothiadiazole, benzovindiflupyr, benzoximate, benzoylprop, benzthiazuron, benzuocaotong, benzyl benzoate, benzyladenine, berber ina, beta-cyfluthrin, beta-cypermethrin, betoxazin, BHC, bialaphos, bicyclopyrone, biphenazate, bifenox, bifentrin, bifujunzhi, bilanaphos, binapacril, bingqingxiao, bioalletrin, bioethanometrin, biopermethrin, bismerthiazolin, biphenyl copper, methylenedi(x-naphthalene-i-sulfonate) bisphenylmercury, bispyribac, bistrifluron, bisultap, bitertanol, bithionol, bixafen, blasticidin-S, borax, Bordeaux mixture, boric acid, boscalid, BPPS, brassinolide, brassinolide-ethyl , brevicomin, brodifacoum, brofenprox, brofenvalerate, broflanilide, broflutrinate, bromacil, bromadiolone, bromclophos, bromethalin, bromethrin, bromfenvinphos, bromoacetamide, bromophenyl, bromobromo, bromo-bromo, bromide -ethyl, bromopropylate, bromothalonil, bromoxynil, brompirazon, bromuconazole, bronopol, BRP, BTH, bucarpolate, bufencarb, buminafos, bupirimate, buprofezin, Burgundy blend, busulfan, busulfan, buta carb, butachlor, butaphenacyl, butam, butamiphos, butanefipronyl, butathiophos, butenachlor, butenefipronil, butethrin, butidazole, butiobate, butyuron, butyphos, butocarboxim, butonate, butopyronoxyl, butoxydim, butulin, butryl butylamine, butylate, butylchlorophos, butylene-fipronil, cacodyl acid, cadusaphos, cafenstrol, calciferol, calcium arsenate, calcium chlorate, calcium cyanamide, calcium cyanide, calcium polysulfide, calvinphos, cambendihlor, camfeclor, camphor , captan, carbam, carbamorph, carbanolate, carbaryl, carbaryl, carbasulam, carbation, carbendazim, carbendazole, carbetamide, carbofenothion, carbofuran, carbon disulfide, carbon tetrachloride, carbonyl sulfide, carbofenothion, carbophos, carbosulfan , carboxazol, carboxyda, carboxin, carfentrazone, carpropamid, cartap, carvacrol, carvone, CAVP, CDAA, CDEA, CDEC, cellocidin, CEPC, ceralure, cerenox, barley, Cheshunt mixture, quinphos, quinphos-methyl, quinomethionate, chinomethionate, chiralaxyl, chitosan, clobenthiazone, clomethoxyphene, chloralose, chloramben, phosphorous chloramine, chloramphenicol, chloraniformtan, chloranil, chloranacryl, chlorantraniliprole, chloraziphor, clorbiron, chlorbiron, chlorbiron , chlordecone, chlordimeform, chlorempentrin, chloretazate, chlorethophon, chloroxyphos, chlorethuron, chlorfenac, chlorfenapyr, chlorfenazol, chlorphenetol, chlorphenidim, chlorfen-prop, chlorfenson, chlorfensulfide, chlorflur- phenyl, chlorflu- r- phenylvin , chlorflurenol, chloridazon, chlorimuron, chlorinate, chlor-IPC, chlormephos, chlormequat, chlormesulone, chlormethoxynil, chlornidine, chlornitrofen, chloroacetic acid, chlorobenzylate, chlorodinitronaphthalenes, chlormequat, chlormesulone, chlorophacinone, chlorophos, chloropicrin, chloropon, chloropropylate, chlorothalonil, chlorotoluron, chloroxyphenidim, chloroxuron, chloroxynil, chlorphonium, chlorphoxim, chlorprazophos, chlorprocarb, chlorprofam, chlorpyrifos, chlorpyriphos-methyl, chlorquinox, chlorsulfuron, chlorthal, chlortiamid, chlorthiophos, chlortoluron, chlorpyriphos, chlorpyriphos-methyl, chlorquinox, chlorsulfuron, chlorthal, chlorthiamide, chlorthiophos, chlortoluron, clozolinate, cyclohexoline, chitosan cimectacarb, cimetacarb, cinerin I, cinerin II, cinerins, cinidon-ethyl, cinmethylin, cinosulfuron, beltfen, ciobutide, cisanilide, cismetrin, claciphos, clefoxidim, clenpyrin, clenpyrin, clodi- dim, climbazole, cliodine cloetocarb, clofencet, clofenotan, clofentezine, clofenvinphos, clofibric acid, clofop, clomazone, climeprop, clonitralid, cloprop, cloproxidim, clopir-lid, cloquintocet, chloransulam, closantel, clomazone, cloxi-mazol, cloxy-CM, cloxi- , CMP, CMU, codlelure, cholecalciferol, rosin, copper 8-quinolinolate, copper acetate, copper acetoarsenite, copper arsenate, basic copper carbonate, copper hydroxide, copper naphthenate, copper oleate copper, copper oxychloride, copper silicate, copper sulphate, basic copper sulphate, copper and zinc chromate, coumachlor, coumaphene, coumafos, coumafuryl, coumafos, coumatetralyl, coumethoxystrobin, coumitoate, coumoxystrobin, CPMC, CPMF , CPPC, credazine, cresol, cresylic acid, crimidine, crotamiton, crotoxifos, crotoxiphos, crufomate, cryolite, cue-lure, cufraneb, cumileron, cumiluron, cuprobam, cuprous oxide, curcumenol, CVMP, cyanphenamide, cyanothrin, cyanophosphate , cyanogen, cyanophos, cyanoate, cyantraniliprol, cyanuric acid, cyazofamid, cibutrine, cyclafuramide, cyclanilide, cyclaniliprol, cicletrin, cycloate, cycloheximide, cycloprate, cycloprotrin, cyclopyrimorate, cyclosulfamuron, cyclo- cluron, cyclethrin, ciflufenamid, ciflumetofen, cifluthrin, cihalofop, cihalotrin, cyhexatin, simiazole, cymoxanil, ciomethrinil, cipendazole, cypermethrin, cyperquat, cifenotrin, cyprazine, cyprazole, ciproconazole, cyprodinil, ciprofuran, ciprofuran prosulfamide, cyromazine, citioate, citrex, daimuron, dalapon, daminozide, dayoutong, dazomet, DBCP, d-camphor, DCB, DCIP, DCPA, DCPTA, DCU, DDD, DDPP, DDT, DDVP, debacarb, decafentin, decafuran, de deet, dehydroacetic acid, deiquat, delachlor, delnav, deltamethrin, demefion, demefion-O, demefion-S, demeton, demeton-methyl, demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyl , demeton-S-methyl sulfone, demeton-S-methyl sulfone, DEP, depalletrin, derris, desmedipham, desmethrin, desmethrin, d-fanshiluquebingjuzhi, diafentiuron, dialipho, dialyphos, diallato, diamidaphos, dianat, diatomaceous earth , diazinon, dibrom, dibutyl phthalate, dibutyl succinate, dicamba, dicapton, dichlobenyl, diclofenthion, diclofluanid, diclone, dichloralurea, dichlorbenzuron, dichlorphenidim, dichlorflurecol, dichlorflurenyl, dichlormidio, dichlormedium, dichlormate , dichlorprop-P, dichlorvos, dichlozolin, dichlozolin, diclobutrazol, diclocimet , diclofop, diclomezine, dichloran, diclosulam, dicofol, dicophan, dicoumarol, dicresyl, dicrotophos, dicrile, dicumarol, dicyclanil, dicyclonon, dieldrin, dienochlor, dietamquat, dietethyl, diethion, diethion, dicarbonate, dietophen , diethyltoluamide, difenacoum, difenoconazole, diphenopenten, difenoxuron, difenzoquat, difethialone, diflovidazin, diflubenzuron, diflufenican, diflufenicanil, diflufenzopyr, diflumethorim, dikegulac, dilor, dimathif, difomexflutrin , dimethane, dimethyrimol, dimethaclone, dimethachlor, dimethamethrin, dimethenamid, dimethenamid-P, dimethenamid, dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate, dimethyl disulfide, dimethyl phthalate, dimethylvinphos, exzonane, dimethylan , dimoxistrobin, dimpilate, dimuron, dinex, dingjunezuo, diniconazole, diniconazol-M, dinitramine, dinitrophenols, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinofenate, dino penton, dinoprop, dinosam, dinoseb, dinosulfon, dinotefuran, dinoterb, dinoterbon, diofenolan, dioxabenzophos, dioxacarb, dioxation, dioxation, difacin, diphacinone, difenadione, difenamid, diphenamide, diphenyl sulfone, diphenylamine, diphenyl dipropalin, dipropetrin, dipterex, dipimethitron, dipyrithion, diquat, disodium tetraborate, disosultap, disparlure, disugran, disul, disulfiram, disulfoton, ditalymphos, dithionon, dithichrophos, dithioether, dithiomethon, dithiopyrone, DM, disulfoton , DMPA, DNOC, dodemorph, dodicin, dodine, dofenapin, doguadin, dominicalure, doramectin, DPC, drazoxolon, DSMA, d-trans-alletrin, d-trans-resmetrin, dufulin, dimron, EBEP, EBP, ebufos, ecdysterone , eclomezole, EDB, EDC, EDDP, edifenphos, eglinazine, emamectin, EMPC, empentrin, enadenine, endosulfan, endothal, endotall, endothion, endrin, enestroburin, enilconazole, enoxastrobin, ephirsulfonate, EPN, epofenazole, epocotin , EPTC erbon, ergocalciferol, erlujixiancaoan, esdepalletrin, esfenvalerate, ESP, esprocarb, etacelasila, etaconazole, etaphos, etem, etaboxam, etachlor, ethalfluralin, etametsulfuron, etapro, etra- thiol, emurtethione , ethirimol, ethoate-methyl, etobenzanid, ethofumesate, ethohexadiol, etoprop, ethoprophos, ethoxyphen, ethoxyquin, ethoxysulfuron, ethiclozate, ethyl formate, ethyl pyrophosphate, ethylan, ethyl-DDD, ethylene, dibromethod , ethylene dichloride, ethylene oxide, ethylicin, ethylmercury 2,3-dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercury bromide, ethylmercury chloride, ethylmercury phosphate, ethynophen, ETM, ethnipromid, ethobenznid, ethoxyazole , etymphos, eugenol, EXD, famoxadone, famfur, fenac, fenamidone, phenaminosulf, fenaminstrobin, fenamiphos, fenapanil, fenarimol, fenasulam, fenazaflor, fenazaquin, fenbuconazol, clofenclofenrazole oxide, fenrfotin , fenclorim, fenetacarb, fenfluthrin, fenfuram, fenhexamid, fenidin, fenitropan, phenitrothion, phenizon, fenjuntong, fenobucarb, fenolovo, fenoprop, phenothiocarb, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop-P, fenoxasulfo- , fenpiclonil, fenpyritrin, fenpropatrin, fenpropidin, fenpropimorph, fenpyrazamine, fenpyroximate, fenquinotrione, fenridazon, fenson, fensulfothion, fenterachol, fentiaprop, fenthion, fenthion-ethyl, fentrifanyl, fentriontin,TC , fenvalerate, ferbam, ferimzone, ferric phosphate, ferrous sulfate, fipronil, flamprop, flamprop-M, flazasulfuron, flocoumafen, flometoquin, flonicamid, florasulam, fluacripirim, fluazifop, fluazifop-P, fluazinam, fluazo- , flubendiamide, flubenzimine, flubrocitrinate, flucarbazone, fluketosulfuron, fluchloralin, flucofuron, flucycloxuron, flucitrinate, fludioxonil, fluenethyl, fluenethyl, fluensulfone, flufenacet, flufenerim, flufenican, flufenoxuron noxistrobin, flufenprox, flufenpyr, fluphenzine, flufiprol, fluhexafon, flumetrin, flumetover, flumetralin, flumetsulam, flumezin, flumiclorac, flumioxazin, flumipropin, flumorf, fluometuron, fluopicolide, fluopyram, fluorfenfluorodioxide, fluoride, fluoroacetide, fluoride , fluoroglycofen, fluoroimide, fluoromide, fluoromidine, fluoronitrofen, fluorooxypyr, fluotiuron, fluotrimazole, fluoxastrobin, flupoxam, flupropacil, flupropadine, flupropanate, flupyradifurone, flupyrsulfuron, fluquinconazole, flurenazole, fluralanerido , fluromidine, fluroxypyr, flurprimidol, flursulamid, flurtamone, flusilazol, flusulfamide, flutenzine, flutiacet, fluthiamide, flutianil, flutolanil, flutriafol, fluvalinate, fluxapiroxad, fluxfenim, folpel, folpet, furon-sulfafen, phonophos , formaldehyde, formetanate, formotion, formparanate, phosamine, fosetyl, fosmethylan, fospirate, phostiazate, fostiet an, frontalin, ft-halide, fuberidazole, fucaojing, fucaomi, fujunmanzhi, fulumi, fumarin, funaihe-caoling, fufenthiourea, furalan, furalaxyl, furametrin, furametpyr, furan tebufenozide, furatiocarb, furcarbanil-furconazole, furconazole , furfural, furilazol, furmeciclox, furophanate, furyloxifen, gamma-BHC, gamma-ci-halothrin, gamma-HCH, genit, gibberellic acid, gibberellin A3, gibberellins, gliftor, glitor, glycochloralose, glufosinate, glufosinate-odin-P, glitor , glyoxime, glyphosate, glyphosin, gossiplure, grandlure, griseofulvin, guanoctine, guazatine, halacrinate, halauxifen, halfenprox, halofenozide, halosafen, halosulfuron, haloxidine, haloxyfop, haloxyfop, Hp-Hp, CB-Haloxy , hemel, hempa, HEOD, heptachlor, heptaflutrin, heptenophos, heeptopargyl, herbimicin, herbimicin A, heterophos, hexachlor, hexachloran, hexachloroacetone, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, hexaflumuron, hexafluoramide, hexalure- hexazin ona, hexylthiophos, hethiazox, HHDN, holosulf, homobrassinolide, huancaiwo, huanchongjing, huangcaoling, huanjunzuo, hydramethylnon, hydrargafen, hydrated lime, hydrogen cyanamide, hydrogen cyanide, hydroprene, hydroxy, IAA, hydroxyazole, IAA IBP, icaridin, imazalil, imazametabenz, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, imazosulfuron, imibenconazole, imiciafos, imidacloprid, imidaclotiz, iminoctadine, imiprotrin, indobflamzino, inabenfida , iodobonil, iodocarb, iodofenphos, iodomethane, iodosulfuron, iofensulfuron, ioxynil, ipazine, IPC, ipconazol, ipfencarbazone, iprobenfos, iprodione, iprovalicarb, iprimidam, ipsdienol, iso- benzol, isol, ipsen, iprodione , isocarbamide, isocarbophos, isocyl, isodrin, isofenphos, isofenphos-methyl, isofetamid, isolan, isomethiozin, isonoruron, isopamphos, isopolinate, isoprocarb, isoprocil, isopropalin, isopropazole, isopropazole isoproturon, isopirazam, isopirimol, isothioate, isothianil, isouron, isovaledione, isoxaben, isoxachlortol, isoxadifen, isoxaflutol, isoxapyrifop, isoxation, isuron, ivermectin, ixoxaben, jamoslin, jamosopamphos jamosaben, jamoslin, jamosopamphos , jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jiecaowan, jiecaoxi, jinganmicin A, jodfenfos, juvenile hormone I, juvenile hormone II, juvenile hormone III, kadetrin, kappa-bifentrin, kappa-teflutrin, karbutilate, karetainele, kasugana ketospiradox, kieselguhr, kinetin, kinoprene, kiralaxyl, kresoxim-methyl, kuicaoxi, lactofen, lambda-ci-halotrin, latilure, lead arsenate, lenacil, lepimectin, leptophos, lianbenjingzhi, lineulin, sulphur, sulfur lirimphos, litlure, looplure, lufenuron, luxiancaolin, lvdingjunzhi, Ivfumijvzhi, Ivxiancaolin, litidation, M-74, M-81, MAA, magnesium phosphide, malathion, maldison, maleic hydrazide, malonoben, maltodextrin, MAMA ncopper, mancozeb, mandestrobin, mandipropamid, maneb, matrin, mazidox, MCC, MCP, MCPA, MCPA-thioethyl, MCPB, MCPP, mebenyl, mecarbam, mecarbinzid, mecarfon, mecoprop, me-coprop-P, medimeform, medilureterb mefenacet, mefenoxam, mefenpyr, mefluidide, megatomoic acid, melissil alcohol, mellitoxin, MEMC, menazon, MEP, mepanipyrim, meperflutrin, mefenate, mephospholan, mepiquat, mepronil, meptildinocap, mercaptodimetur, mercaptophostion, mercaptophostion , mercuric chloride, mercuric oxide, mercuric chloride, merphos, merphos oxide, mesoprazine, mesosulfuron, mesotrione, mesulfen, mesulfenphos, mesulfen, metacresol, metaflumizone, metalaxyl, metalaxyl-M, metaldehyde, metam, metamifop, metamitron, metaphos, metaxon, metazachlor, metazosulfuron, metazoxolon, metconazol, metepa, metflurazon, metabenzthiazuron, methacrylophs, metalpropalin, metam, metamidophos, metasulfocarb, methazol, met-furoxam, methibenzuron, methi- thiocarben risul furon, methiotepa, methiozolin, methyuron, methocrotophos, metolcarb, methomethon, methomyl, methoprene, methoprothrin, methoprothrin, methoquin-butyl, methothrin, methoxichlor, methoxyphenozide, methoxyphenone, methyl methyl methothione, methyl methothiol, methyl methothione, methyl methothiol, bromethol , methyl isothiocyanate, methyl parathion, methylacetophos, methylchloroform, methyldithiocarbamic acid, methyldimron, methylene chloride, methylisofenphos, methylmercaptofos, methylmercaptophos oxide, methylmercaptophosthiol-thiolmercurium, methylphencurium methylphencurium methyl benzoate , methylneodecanamide, methylnitrofos, methyltriazothion, methiozolin, metiram, metiram-zinc, methobenzuron, methobromuron, metoflutrin, metolachlor, metolcarb, metometuron, metomi- nostrobin, metosulam, methoxadiazone, methobenzuron, methobromuron - ron, mevinphos, mexacarbate, miechuwei, mieshuan, miewenjuzhi, mil-benectin, milbemicin oxime, milneb, m ima2nan, mipafox, MIPC, mirex, MNAF, moguchun, molinate, molosultap, momfluorotrin, monalide, monisuron, monoamitraz, monochloroacetic acid, monocrotofos, monolinuron, monomehipo, monosulfiram, monosulfuron, monosultap, TCquaron , moroxidine, morphotion, morzid, moxidectin, MPMC, MSMA, MTMC, muscalure, myclobutanil, myclozolin, myricyl alcohol, N-(ethylmercury)-p-toluenesulfonanilide, NAA, NAAm, nabam, naphthalophos, naled, naphthalene, naphthalic anhydride, naphthalophos, naphthoxyacetic acids, naphthylacetic acids, naphthylindane-1,3-diones, naphthyloxyacetic acids, naproanilide, napropamide, napropamide-M, naptalam, natamicin, NBPOS, neburea, neburon, nendrin, neonicotine, niclofen, niclosamide, nicobifen, nicosulfuron, nicotine, nicotine sulfate, nifluridide, nikkomicins, NIP, nipyraclofen, nipiralofen, nitenpyram, nithiazine, nitralin, nitrapirin, nitrilacarb, nitrofen, nitrostyrene, nitrofen la, nobormide, nonanol, norbormide, norea, norflurazon, nornicotine, noruron, novaluron, noviflumuron, NPA, nuarimol, nuranone, OCH, octachlorodipropyl ether, octylinone, o-dichlorobenzene, ofurace, omethoate, o-phenylphenol, orbencarb , orfralure, ortobencarb, ortho-dichlorobenzene, orthosulfamuron, orictalure, orisastrobin, orizalin, ostol, ostole, ostramone, ovatron, ovex, oxabetrinil, oxadiargyl, oxadiazon, oxadixyl, oxamate, oxazixapyrazon, oxa- pyrazon , oxine-copper, oxine-Cu, oxolinic acid, oxpoconazole, oxycarboxin, oxydemeton-methyl, oxideprofos, oxidisulfoton, oxyenadenine, oxyfluorfen, oxithrin, oxytetracycline, oxythioquinox, PAC, paclong-t-rading, paicho dichlorobenzene, parafluron, paraquat, parathion, parathion-methyl, parinol, Paris green, PCNB, PCP, PCP-Na, p-dichlorobenzene, PDJ, pebulate, pedinex, pefurazoate, pelargonic acid, penconazole, pencicuron, pendimethalin, penfenate, penfluf en, penfluron, penoxalin, penoxsulam, pentachlorophenol, pentachlorophenyl laurate, pentanochlor, penthiopyrad, pentmetrin, pentoxazone, perchlordecon, perfluidone, permethrin, petoxamid, PHC, phenamacryl, phenamacryl-sulfazine oxide, fe fenetacarb, fenisofam, fenkapton, phenmedipham, phenmedipham-ethyl, phenobenzuron, phenothiol, phenothrin, fenprooxide, phentoate, phenylmercuryurea, phenylmercury acetate, phenylmercury chloride, phenylmercuric derivative of phenylmercurium nitrate, pyrocatechol pyrumeric nitrate, phenylmercuric nitrate , phosacetin, phosalone, phosmethine, fosazetim, fosazetin, phoscyclotin, phosdifen, fosetyl, phospholan, phospholan-methyl, phosglycin, phosmet, phosnichlor, phosphamide, phosphamidon, phosphine, phosphinotricin, phosphocarb, phosphorus, fostin -methyl, phthalide, phthalophos, phthaltrin, picarbutrazox, picaridin, picloram, picolinafen, pico-xistrobin, pimaricin, pindone, pinoxaden, piperalin, piperazine, piperonyl butoxide, piperonyl cyclon ene, piperophos, piproctanli, piproctanil, piprotal, pyrimetaphos, pirimicarb, pyriminil, pirimioxiphos, pirimiphos-ethyl, pirimiphos-methyl, pival, pivaldione, plifenate, PMA, PMP, polybutenes, polycarbamate, polyethoxynamphen , polyoxorim, politialan, potassium arsenite, potassium azide, potassium cyanate, potassium ethylxanthate, potassium naphthenate, potassium polysulfide, potassium thiocyanate, pp'-DDT, pralletrin, precocious I, precocious II, precocious III, pretilachlor, primidophos, primisulfuron, probenazol, prochloraz, proclonol, procyazine, procymidone, prodiamine, profenofos, profluazol, profluralin, proflutrin, profoxidim, profurita-aminium, proglinazine, prohexadione, prohydrojasmon, procarmacyl prometon, promethrin, promethrin, promurit, pronamide, propachlor, propaphos, propamidine, propamocarb, propanil, propaphos, propaquizafop, propargite, proparthrin, propazine, propetamphos, profam, propiconazol, propidi na, propineb, propisochlor, propoxur, propoxycarbazone, propylisome, propyrissulfuron, propizamide, proquinazid, prosuler, prosulfalin, prosulfocarb, prosulfuron, protidation, prothiocarb, prothioconazole, prothiophos, protocloate, proxan- enbute , psoralen, pidanon, piflubumide, pymetrozine, pyracarbolid, pyraclophos, pyraclonil, pyraclostrobin, pyraflufen, pyrafluprol, piramat, pirametostrobin, pyraoxystrobin, pyrasulfotol, pyraziflumid, pyrazolate, pylostrobin, pyrazofen, pirazofen , Pyrethrin I, Pyrethrin II, Pyrethrins, Pyribambenz-isopropyl, Pyribambenz-propyl, Pyribencarb, Pyribenzoxim, Pyributicarb, Pyrichlor, Pyridaben, Pyridafol, Pyridalyl, Pyridafenthion, Pyridaphenthione, Pyridate, Pyribenzoxim, Pyribenthryl, Pyribenthyl , pyrimethanil, pirimicarb, pyrimidifen, pyriminobac, pyriminostrobin, pyrimiphos-ethyl, pyrimiphos-methyl, pyrimisulfan, pyrimitate, pyr inuron, pyriophenone, pyriprole, pyripropanol, pyriproxyfen, pyrisoxazole, pyrithiobac, pyrolan, pyroquilon, pyroxasulfone, piroxsulam, pyroxychlor, piroxifur, quincaosuan, qingkuling, quassia, quinacetol, quinphos, quinazole, quinazole-methyl quinmerac, quinocamine, quinomethionate, quinonamid, quinothion, quinoxyfen, quinthiophos, quintazene, quizalofop, quizalofop-P, quwenzhi, quyingding, rabenzazol, rafoxanide, R-diniconazole, rebemide, rodetanuril, rescalronin, rescalrid rodojaponin-III, ribavirin, rimsulfuron, rizazol, R-metalaxyl, rodétanil, ronnel, rotenone, riania, sabadilla, saflufenacil, saijunmao, saisentong, salicilanilide, salifluofen, sanguinarine, santonin, S-bioalletrin, schradan, sebuziros sedaxane, selamectin, semimitraz, sesamex, sesamolin, sesone, sethoxidim, sevin, shuangjiaancaolin, shuangjianancaolin, S-hydroprene, siduron, sifumijvzhi, siglure, silafluofen, silatrane, silica airgel , silica gel, siltiofam, siltiopham, siltiophan, silvex, simazine, simeconazole, simeton, simetrin, simetrine, syntofen, S-kinoprene, slaked lime, SMA, S-methoprene, S-metolachlor, sodium arsenite, sodium azide , sodium chlorate, sodium cyanide, sodium fluoride, sodium fluoroacetate, sodium hexafluorosilicate, sodium naphthenate, sodium o-phenylphenoxide, sodium orthophenylphenoxide, sodium pentachlorophenate, sodium pentachlorophenoxide, sodium polysulfide, silicofluoride sodium, sodium tetrathiocarbonate, sodium thiocyanate, solan, sofamide, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine, styrophos, streptomycin, strychnine, sulcatol, sulcofuron, sulcotrione, sulfallate, sulfentrazone , sulfluramid, sulfodiazole, sulfometuron, sulfosate, sulfosulfuron, sulfotep, sulfotepp, sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid, sulfuryl fluoride, sulglicapin, sulfosate, sulprofos, sultropen, swep alinate, tavron, tazimcarb, TBTO, TBZ, TCA, TCBA, TCMTB, TCNB, TDE, tebuconazole, tebufenozide, tebufenpyrad, tebufloquin, tebupyrimfos, tebutam, tebutiuron, teclophthalam, tebufenozide, tebufenozide, tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebutiuron, teclophthalam, tebufenozide, tebufenazen, tefuryltrione, tembotrione, temephos, temephos, tepa, TEPP, tepraloxidim, teproloxydim, teralletrin, terbacil, terbucarb, terbuchlor, terbufos, terbumeton, terbuthylazine, terbutol, terbutrin, terbutrine, terrachloremycin, tethermicin tetrachlorvinphos, tetraconazole, tetradiphon, tetradisul, tetrafluron, tetramethrin, tetramethylfluthrin, tetraamine, tetranactin, tetraniliprol, tetrapion, tetrasul, thallium sulfate, thallus sulfate, tenylchlor, teta-cypermethrin, thiabendazole, thiacloprid, thidiazine, thiamethuron, , thiapronil, thiazafluron, thiazfluron, thiazone, thiazopyr, ticrophos, ticiofen, tidiazimin, tidiazuron, thiencarbazone, thifensulfuron, tifluzamide, thimerosal, timet, thiobencarb, thiocarboxime, thiochlorfen finally, thiochlorphenphime, thiocyanatodinitrobenzenes, thiocyclam, thiodan, thiodiazol-copper, thiodicarb, thiophanocarb, thiophanox, thiofluoximate, thiohempa, thiomersal, thiomethon, thionazin, thiophanate, thiophanato-thio-methyl, thiophate osemicarbazide, tiosultap, thiotepa, thioxamyl, tiram, thiuram, turingiensin, thiabendazole, tiadinil, thifenacyl, tiaojiean, TIBA, thifatol, thiocarbazil, thiochlorim, thioxazafen, thioximid, tolprol- tolprob, tyrpato tolifluanid, tolylfluanid, tolylmercury acetate, tomarin, topramezone, toxaphene, TPN, tralkoxidim, tralocitrin, tralomethrin, tralopyril, transfluthrin, transpermethrin, tretamine, triacontanol, tria-dimefon, triadimenol, tria- phamona, triphamona, triapentenol, triarathene, triarimol, triasulfuron, triazamate, triazbutyl, triaziflam, triazophos, triazothion, triazoxide, tribasic copper chloride, tribasic copper sulfate, tribenuron, tribufos, tributile oxide tin, tricamba, triclamide, triclopyr, trichlorphon, trichlormetaphos-3, trichloronat, trichloronate, trichlorotrinitrobenzenes, trichlorphon, triclopi, triclopyricarb, tricresol, tricyclazole, tricyclohexyltin hydroxide, tridemorph, tridiphane, tri- trophine, tri- trophazine trifloxysulfuron, trifludimoxazin, triflumezopyrim, triflumizole, triflumuron, trifluralin, triflusulfuron, trifop, trifopsime, triforine, trihydroxytriazine, trimedlure, trimetacarb, trimeturon, trinexapac, triphenyltin, tripropyn, tripren, trine tritosulfuron, trunc-call, tuoielin, uniconazol, uniconazol-P, urbacida, uredepa, valerate, validamycin, validamycin A, valifenalate, valone, vamidothion, vangard, vaniliprol, vernolate, vinclozolin, vitamin D3, warfarin, xinjunan, xiwojunan, xiwojunzhi, XMC, xylachlor, xylenols, xylylcarb, ximiazol, yishijing, zarilamid, zeatin, zengxiaoan, zengxiaolin, zeta-cypermethrin, na zinc phthenate, zinc phosphide, zinc thiazole, zinc thiazole, zinc trichlorophenate, zinc trichlorophenoxide, zineb, ziram, zolaprofos, zoocoumarin, zoxamide, zuoanjunzhi, zuocaoan, zuojunzhi, zuomihuangdisinone, α-chlorohydrinone, α- multistriatin, a-naphthaleneacetic acids and β-ecdysone; (2) the following molecules (a) N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N- ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide (hereinafter "AI-1")
Figure img0001
(b) (3S,6S,7R,8R)-8-benzyl-3-(3-((iso-butyryloxy)methoxy)-4-methoxypicolinamido)-6-methyl-4,9-dioxo-1,isobutyrate 5-dio-xonan-7-yl (hereinafter "AI-2")
Figure img0002
(3) a molecule known as Lotilaner which has the following structure
Figure img0003
(4) the following molecules in Table ATable A - Structure of M# - active ingredients
Figure img0004
Figure img0005

[00012] Como usado nesta descrição, cada um dos acima é um princípio ativo. Para mais informações consulte o "Compendium of Pesticide Common Names" localizado em Alanwood.net e várias edições, incluindo a edição online do "The Pesticide Manual" localizado em bcpcdata.com.[00012] As used in this description, each of the above is an active ingredient. For more information see the "Compendium of Pesticide Common Names" located at Alanwood.net and various editions, including the online edition of "The Pesticide Manual" located at bcpcdata.com.

[00013] Uma seleção particularmente preferencial de princípios ativos é 1,3-dicloropropeno, clorpirifos, hexaflumuron, metoxifenozida, novi- flumuron, espinetoram, spinosad e sulfoxaflor (doravante "AIGA-2").[00013] A particularly preferred selection of active ingredients is 1,3-dichloropropene, chlorpyrifos, hexaflumuron, methoxyfenozide, noviflumuron, spinetoram, spinosad and sulfoxaflor (hereinafter "AIGA-2").

[00014] Adicionalmente, outra seleção particularmente preferencial de princípios ativos é acequinocila, acetamiprid, acetoprol, avermectin, azinfos-metila, bifenazato, bifentrin, carbarila, carbofuran, clorfenapir, clorfluazuron, cromafenozida, clotianidin, ciflutrin, cipermetrin, deltame- trin, diafentiuron, benzoato de emamectin, endosulfan, esfenvalerato, etiprol, etoxazol, fipronila, flonicamid, fluacripirim, gama-cialotrin, halo- fenozida, indoxacarb, lambda-cialotrin, lufenuron, malation, metomila, novaluron, permetrin, piridalila, pirimidifen, spirodiclofen, tebufenozida, tiacloprid, tiametoxam, tiodicarb, tolfenpirad, e zeta-cipermetrin (dora-vante "AIGA-3").[00014] Additionally, another particularly preferred selection of active principles is acequinocyl, acetamiprid, acetoprol, avermectin, azinphos-methyl, biphenazate, bifentrin, carbaryl, carbofuran, chlorfenapyr, chlorfluazuron, chromafenozide, clothianidin, ciflutrin, delta-cypermethrin , emamectin benzoate, endosulfan, esfenvalerate, etiprol, etoxazol, fipronil, flonicamid, fluacripyrim, gamma-cyalotrin, halofenozide, indoxacarb, lambda-cyhalothrin, lufenuron, malation, methomyl, novaluron, permethrin, pyridindicidalil, , thiacloprid, thiamethoxam, thiodicarb, tolfenpyrad, and zeta-cypermethrin (hereinafter "AIGA-3").

[00015] O termo "alquenila" significa um substituinte acíclico insa- turado (pelo menos uma ligação dupla carbono-carbono) ramificado ou não consistindo em carbono e hidrogênio, por exemplo, vinila, alila, butenila, pentenila e hexenila.[00015] The term "alkenyl" means an unsaturated acyclic substituent (at least one carbon-carbon double bond) branched or not consisting of carbon and hydrogen, eg vinyl, allyl, butenyl, pentenyl and hexenyl.

[00016] O termo "alquenilóxi" significa um alquenila consistindo adicionalmente em uma ligação simples carbono-oxigênio, por exemplo, alilóxi, butenilóxi, pentenilóxi, hexenilóxi.[00016] The term "alkenyloxy" means an alkenyl additionally consisting of a single carbon-oxygen bond, eg allyloxy, butenyloxy, pentenyloxy, hexenyloxy.

[00017] O termo "alcóxi" significa um alquil consistindo adicionalmente em uma ligação simples carbono-oxigênio, por exemplo, metó- xi, etóxi, propóxi, isopropóxi, butóxi, isobutóxi, e terc-butóxi.[00017] The term "alkoxy" means an alkyl additionally consisting of a single carbon-oxygen bond, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tert-butoxy.

[00018] O termo "alquila" significa um substituinte acíclico saturado ramificado ou não consistindo em carbono e hidrogênio, por exemplo, metila, etila, propila, isopropila, butila e terc-butila.[00018] The term "alkyl" means a branched or unbranched saturated acyclic substituent consisting of carbon and hydrogen, for example, methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.

[00019] O termo "alquinila" significa um substituinte acíclico insatu- rado (pelo menos uma ligação tripla carbono-carbono) ramificado ou não consistindo em carbono e hidrogênio, por exemplo, etinila, propar- gila, butinila, pentinila.[00019] The term "alkynyl" means an unsaturated acyclic substituent (at least one carbon-carbon triple bond) branched or not consisting of carbon and hydrogen, eg ethynyl, propargyl, butynyl, pentynyl.

[00020] O termo "alquinilóxi" significa um alquinil consistindo adi-cionalmente em uma ligação simples carbono-oxigênio, por exemplo, pentinilóxi, hexinilóxi, heptinilóxi e octinilóxi.[00020] The term "alkynyloxy" means an alkynyl consisting in addition of a single carbon-oxygen bond, for example, pentynyloxy, hexynyloxy, heptynyloxy and octynyloxy.

[00021] O termo "arila" significa um substituinte cíclico aromático consistindo em hidrogênio e carbono, por exemplo, fenila, naftila e bi- fenila.[00021] The term "aryl" means an aromatic cyclic substituent consisting of hydrogen and carbon, for example, phenyl, naphthyl and biphenyl.

[00022] O termo "biopesticida" significa um agente de controle de pragas biológico microbiano que, em geral, é aplicado de uma maneira semelhante a pesticidas químicos. Comumente, eles são bacterianos, mas também há exemplos de agentes de controle fúngicos, incluindo Trichoderma spp. e Ampelomyces quisqualis. Um exemplo de biopes- ticida bem conhecido é a espécie Bacillus, uma doença bacteriana de Lepidoptera, Coleoptera e Diptera. Biopesticidas incluem produtos à base de fungos entomopatogênicos (por exemplo, Metarhizium aniso- pliae), nematódeos entomopatogênicos (por exemplo, Steinernema feltiae) e vírus entomopatogênicos (por exemplo, granulovírus Cydia pomonella). Outros exemplos de organismos entomopatogênicos incluem, mas não estão limitados a, baculovírus, protozoários e Microsporidia. Para evitar dúvidas, biopesticidas são princípios ativos.[00022] The term "biopesticide" means a microbial biological pest control agent that is generally applied in a similar manner to chemical pesticides. They are commonly bacterial, but there are also examples of fungal control agents, including Trichoderma spp. and Ampelomyces quisqualis. An example of a well-known biopesticide is Bacillus species, a bacterial disease of Lepidoptera, Coleoptera and Diptera. Biopesticides include products based on entomopathogenic fungi (eg Metarhizium anisopliae), entomopathogenic nematodes (eg Steinernema feltiae) and entomopathogenic viruses (eg Cydia pomonella granulovirus). Other examples of entomopathogenic organisms include, but are not limited to, baculoviruses, protozoa and Microsporidia. For the avoidance of doubt, biopesticides are active ingredients.

[00023] O termo "cicloalquenila" significa um substituinte monocí- clico ou policíclico insaturado (pelo menos uma ligação dupla carbono- carbono) consistindo em carbono e hidrogênio, por exemplo, ciclobu- tenila, ciclopentenila, ciclo-hexenila, norbornenila, biciclo[2.2.2]octenila, tetra-hidronaftila, hexa-hidronaftila e octa-hidronaftila.[00023] The term "cycloalkenyl" means an unsaturated monocyclic or polycyclic substituent (at least one carbon-carbon double bond) consisting of carbon and hydrogen, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, bicyclo[ 2.2.2]octenyl, tetrahydronaphthyl, hexahydronaphthyl and octahydronaphthyl.

[00024] O termo "cicloalquenilóxi" significa um cicloalquenil consistindo adicionalmente em uma ligação simples carbono-oxigênio, por exemplo, ciclobutenilóxi, ciclopentenilóxi, norbornenilóxi e bici- clo[2.2.2]octenilóxi.[00024] The term "cycloalkenyloxy" means a cycloalkenyl additionally consisting of a single carbon-oxygen bond, for example, cyclobutenyloxy, cyclopentenyloxy, norbornenyloxy and cyclo[2.2.2]octenyloxy.

[00025] O termo "cicloalquila" significa um substituinte monocíclico ou policíclico saturado consistindo em carbono e hidrogênio, por exemplo, ciclopropila, ciclobutila, ciclopentila, norbornila, biciclo[2.2.2] metoxicinamato e deca-hidronaftila.[00025] The term "cycloalkyl" means a saturated monocyclic or polycyclic substituent consisting of carbon and hydrogen, for example, cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, bicyclo[2.2.2] methoxycinnamate and decahydronaphthyl.

[00026] O termo "cicloalcóxi" significa um cicloalquil consistindo adicionalmente em uma ligação simples carbono-oxigênio, por exemplo, ciclopropilóxi, ciclobutilóxi, ciclopentilóxi, norbornilóxi e bici- clo[2.2.2]octilóxi.[00026] The term "cycloalkoxy" means a cycloalkyl additionally consisting of a single carbon-oxygen bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, norbornyloxy and cyclo[2.2.2]octyloxy.

[00027] O termo "halo" significa flúor, cloro, bromo e iodo.[00027] The term "halo" means fluorine, chlorine, bromine and iodine.

[00028] O termo "haloalcóxi" significa um alcóxi consistindo adici-onalmente em de um até o número máximo possível de halos idênticos ou diferentes, por exemplo, fluorometóxi, trifluorometóxi, 2,2-difluoro- propóxi, clorometóxi, triclorometóxi, 1,1,2,2-tetrafluoroetóxi e pentaflu- oroetóxi.[00028] The term "haloalkoxy" means an alkoxy additionally consisting of one to the maximum possible number of identical or different halos, for example, fluoromethoxy, trifluoromethoxy, 2,2-difluoropropoxy, chloromethoxy, trichloromethoxy, 1, 1,2,2-tetrafluoroethoxy and pentafluoroethoxy.

[00029] O termo "haloalquila" significa um alquil consistindo adici-onalmente em um até o número máximo possível de halos idênticos ou diferentes, por exemplo, fluorometila, trifluorometila, 2,2-difluoropro- pila, clorometila, triclorometila, e 1,1,2,2-tetrafluoroetila.[00029] The term "haloalkyl" means an alkyl additionally consisting of one to the maximum possible number of identical or different halos, for example, fluoromethyl, trifluoromethyl, 2,2-difluoropropyl, chloromethyl, trichloromethyl, and 1, 1,2,2-tetrafluoroethyl.

[00030] O termo "heterociclila" significa um substituinte cíclico que pode ser aromático, totalmente saturado, ou parcial ou totalmente in- saturado, onde a estrutura cíclica contém pelo menos um carbono e pelo menos um heteroátomo, onde dito heteroátomo é nitrogênio, enxofre ou oxigênio. Exemplos são:(1) substituintes aromáticos heterociclila incluem, mas não estão limitados a, benzofuranila, benzoisotiazolila, benzoiso- xazolila, benzotienila, benzotiazolila, benzoxazolila, cinolinila, furanila, imidazolila, indazolila, indolila, isoindolila, isoquinolinila, isotiazolila, isoxazolila, oxadiazolila, oxazolinila, oxazolila, ftalazinila, pirazinila, pi- razolinila, pirazolila, piridazinila, piridila, pirimidinila, pirrolila, quinazoli- nila, quinolinila, quinoxalinila, tetrazolila, tiazolinila, tiazolila, tienila, tri- azinila e triazolila;(2) substituintes heterociclila totalmente saturados incluem, mas não estão limitados a, piperazinila, piperidinila, morfolini- la, pirrolidinila, tetra-hidrofuranila, tetra-hidropiranila, tetra-hidrotiofe- nila, tetra-hidrotiofenilóxido, tetra-hidrotiofenildióxido; (3) substituintes heterociclila parcialmente ou to-talmente insaturados incluem, mas não estão limitados a, 4,5-di- hidro-isoxazolila, 4,5-di-hidro-oxazolila, 4,5-di-hidro-1 H-pirazolila, 2,3-di-hidro-[1,3,4]-oxadiazolila, 2,5-dioxoimidazolidinila, 2,4-dioxo- 1,3-diazaspiro[4.4]nonanilisoxazolidinonila, oxazolidinonila, imidazoli- dinonila, isoxazolidinonila, pirrolidinonila, 1,2,3,4-tetra-hidro-quinolinila e tioxotiazolidinonila; e(4) Exemplos adicionais de heterociclis incluem os se-guintes:

Figure img0006
[00030] The term "heterocyclyl" means a cyclic substituent that can be aromatic, fully saturated, or partially or fully unsaturated, where the cyclic structure contains at least one carbon and at least one heteroatom, where said heteroatom is nitrogen, sulfur or oxygen. Examples are: (1) heterocyclyl aromatic substituents include, but are not limited to, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, cinolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoindolyl, isoquinoyl oxazolinyl, isoquinoyl, isoxazolinyl , oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolinyl, thiazolyl, thienyl, triazolinyl(2) and heterocyclyl(2) substituents; fully saturated include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiophenyloxide, tetrahydrothiophenyldioxide; (3) partially or fully unsaturated heterocyclyl substituents include, but are not limited to, 4,5-dihydro-isoxazolyl, 4,5-dihydro-oxazolyl, 4,5-dihydro-1H- pyrazolyl, 2,3-dihydro-[1,3,4]-oxadiazolyl, 2,5-dioxoimidazolidinyl, 2,4-dioxo-1,3-diazaspiro[4.4]nonanilisoxazolidinonyl, oxazolidinonyl, imidazolidinonyl, isoxazolidinonyl, pyrrolidinonyl, 1,2,3,4-tetrahydro-quinolinyl and thioxothiazolidinonyl; and (4) Additional examples of heterocyclyls include the following:
Figure img0006

[00031] O termo "locus" significa um hábitat, terreno de reprodução, planta, semente, solo, material ou ambiente no qual uma praga cresce, pode crescer ou pode atravessar. Por exemplo, um locus pode ser: onde culturas, árvores, frutos, cereais, espécies de forragem, vinhas, relva e/ou plantas ornamentais crescem; onde animais domesticados residem; superfícies interiores ou exteriores de edifícios (tais como lugares onde grãos são armazenados); os materiais de construção usados em edifícios (tais como madeira impregnada); e o solo em torno de edifícios.[00031] The term "locus" means a habitat, breeding ground, plant, seed, soil, material or environment in which a pest grows, can grow or can cross. For example, a locus can be: where crops, trees, fruits, cereals, forage species, vines, grass and/or ornamental plants grow; where domesticated animals reside; interior or exterior surfaces of buildings (such as places where grain is stored); the construction materials used in buildings (such as impregnated wood); and the ground around buildings.

[00032] A frase "Material MoA" significa um princípio ativo com um modo de ação ("MoA") como indicado na Classificação IRAC MoA v. 7.3, localizada em irac-online.org., que descreve os seguintes grupos.(1) Inibidores da acetilcolinesterase (AChE), inclui os seguintes princípios ativos: alanicarb, aldicarbe, bendiocarb, benfura- carb, butocarboxim, butoxicarboxim, carbarila, carbofuran, carbosulfan, etiofencarb, fenobucarb, formetanato, furatiocarb, isoprocarb, metio- carb, metomila, metolcarb, oxamila, pirimicarb, propoxur, tiodicarb, tio- fanox, triazamato, trimetacarb, XMC, xililcarb, acefato, azametifos, azinfos-etila, azinfos-metila, cadusafos, cloretoxifos, clorfenvinfos, clormefos, clorpirifos, clorpirifos-metila, coumafos, cianofos, demeton- S-metila, diazinon, diclorvos/DDVP, dicrotofos, dimetoato, dimetilvin- fos, disulfoton, EPN, etion, etoprofos, famfur, fenamifos, fenitrotion, fention, fostiazato, heptenofos, imiciafos, isofenfos, salicilato de iso- propil O-(metoxiaminotio-fosforila), isoxation, malation, mecarbam, metamidofos, metidation, mevinfos, monocrotofos, naled, ometoato, oxidemeton-metila, paration, paration-metila, fentoato, forato, fosalo- na, fosmet, fosfamidon, foxim, pirimifos-metila, profenofos, propetam- fos, protiofos, piraclofos, piridafention, quinalfos, sulfotep, tebupirimfos, temefos, terbufos, tetraclorvinfos, tiometon, triazofos, triclorfon, vami- dotion.(2) antagonistas do canal de cloreto mediado por GABA, inclui os seguintes princípios ativos: clordano, endossulfan, etiprol e fipronil.(3) Moduladores de canais de sódio, inclui os seguintes princípios ativos: acrinatrin, alletrin, d-cis-trans alletrin, d-trans alletrin, bifentrin, bioalletrin, bioalletrin S-ciclopentenila, bioresmetrin, cicloprotrin, ciflutrin, beta-ciflutrin, cialotrin, lambda-cialotrin, gama- cialotrin, cipermetrin, alfa-cipermetrin, beta-cipermetrin, teta-ciperme- trin, zeta-cipermetrin, cifenotrin [(1R)-trans-isômeros], deltametrin, [(EZ)-(1R)-isômeros] de empentrin, esfenvalerato, etofenprox, fenpro- patrin, fenvalerato, flucitrinato, flumetrin, tau-fluvalinato, halfenprox, imiprotrin, kadetrin, permetrin, [(1R)-trans-isômero] de fenotrin, pralle- trin, piretrins (piretro), resmetrin, silafluofen, teflutrin, tetrametrin, [(1R)- isômeros] de tetrametrin, tralometrin e transflutrin e metoxiclor.(4) Agonistas do receptor nicotínico de acetilcolina (nA- ChR), inclui os seguintes princípios ativos: (4A) acetamiprida, clotianidin, dinotefuran, imidacloprid, ni- tenpiram, tiacloprid, tiametoxam,(4B) nicotina,(4C) sulfoxaflor,(4D) flupiradifurona,(4E) triflumezopirim e dicloromezotiaz.(5) Ativadores alostéricos do receptor nicotínico de acetilcolina (nAChR), inclui os seguintes princípios ativos: espineto- ram e spinosad.(6) Ativadores do canal de cloreto, inclui os seguintes princípios ativos: abamectin, benzoato de emamectin, lepimectin e mil- bemectin.(7) Simuladores de hormônio juvenil, inclui os seguintes princípios ativos: hidropreno, kinopreno, metopreno, fenoxicarb e piri- proxifen.(8) Miscelânea de inibidores não específicos (multissí- tios), inclui os seguintes princípios ativos: brometo de metila, cloropi- crina, fluoreto de sulfurila, bórax e tártaro emético.(9) Moduladores de Órgãos Cordotonais, inclui os se-guintes princípios ativos: pimetrozina e flonicamid.(10) Inibidores do crescimento de ácaros, inclui os se-guintes princípios ativos: clofentezina, hexitiazox, diflovidazin e etoxa- zol.(11) Disruptores microbianos de membranas mesentéri- cas de insetos, inclui os seguintes princípios ativos: Bacillus thuringien- sis subsp. Israelensis, Bacillus thuringiensis subsp. aizawai, Bacillus thu- ringiensis subsp. Kurstaki, Bacillus thuringiensis subsp. tenebrionenis, proteínas de cultura Bt (Cry1Ab, Cry1Ac, Cry1Fa, Cry1A.105, Cry2Ab, Vip3A, mCry3A, Cry3Ab, Cry3Bb, Cry34Ab1/Cry35Ab1) e Bacillus sphaericus. (12) Inibidores de ATP sintase mitocondrial, inclui os seguintes princípios ativos: tetradifon, propargita, azocicloestanho, ci- hexaestanho, óxido de fenbutaestanho e diafentiuron.(13) Desacopladores da fosforilação oxidativa através da disrupção do gradiente de prótons, inclui os seguintes princípios ativos: clorfenapir, DNOC e sulfluramid.(14) Bloqueadores do canal do receptor nicotínico de acetilcolina (nAChR), inclui os seguintes princípios ativos: bensultap, cloridrato de cartap, tiociclam e tiosultap-sódio.(15) Inibidores da biossíntese de quitina, tipo 0, inclui os seguintes princípios ativos: bistrifluron, clorfluazuron, diflubenzuron, flucicloxuron, flufenoxurom, hexaflumuron, lufenuron, novaluron, novi- flumuron, teflubenzuron e triflumuron.(16) Inibidores da biossíntese de quitina, tipo 1, inclui o seguinte princípio ativo: buprofezin.(17) Disruptor de muda Dipteran, inclui o seguinte princí-pio ativo: ciromazina.(18) Agonistas do receptor de ecdisona, inclui os seguintes princípios ativos: cromafenozida, halofenozida, metoxifenozida e tebufenozida.(19) Agonistas do receptor de octopamina, inclui o se-guinte princípio ativo: amitraz.(20) Inibidores do transporte de elétrons do complexo III mitocondrial, inclui os seguintes princípios ativos hidrametilnon, acequinocil e fluacripirim.(21) Inibidores do transporte de elétrons do complexo I mitocondrial, inclui os seguintes princípios ativos: fenazaquin, fenpi- roximato, pirimidifen, piridaben, tebufenpirad, tolfenpirad e rotenona.(22) Bloqueadores dos canais de sódio dependentes de voltagem, inclui os seguintes princípios ativos: indoxacarb e me- taflumizona.(23) Inibidores da acetil CoA carboxilase, inclui os seguintes princípios ativos: espirodiclofen, espiromesifen e espirotetramat.(24) Inibidores do transporte de elétrons do complexo IV mitocondrial, inclui os seguintes princípios ativos: fosfeto de alumínio, fosfeto de cálcio, fosfina, fosfeto de zinco e cianeto.(25) Inibidores do transporte de elétrons do complexo II mitocondrial, inclui os seguintes princípios ativos: cienopirafen e ci- flumetofen. e(28) Moduladores do receptor de rianodina, inclui os seguintes princípios ativos: clorantraniliprol, ciantraniliprol e fluben- diamida.[00032] The phrase "Material MoA" means an active ingredient with a mode of action ("MoA") as indicated in IRAC Classification MoA v. 7.3, located at irac-online.org., which describes the following groups.(1) Acetylcholinesterase (AChE) inhibitors, includes the following active principles: alanicarb, aldicarb, bendiocarb, benfura-carb, butocarboxim, butoxycarboxim, carbaryl, carbofuran , carbosulfan, ethiofencarb, fenobucarb, formetanate, furatiocarb, isoprocarb, methiocarb, methomyl, metolcarb, oxamyl, pirimicarb, propoxur, thiodicarb, thiophanox, triazamate, trimetacarb, XMC, xylyl-asethys, ainfoso, acephate -methyl, cadusaphos, chloroxiphos, chlorfenvinphos, chlormephos, chlorpyrifos, chlorpyrifos-methyl, coumaphos, cyanophos, demeton-S-methyl, diazinon, dichlorvos/DDVP, dicrotophos, dimethoate, dimethylvinphos, phomphothione, esulfoton , fenamiphos, fenitrothion, fenthion, phosthiazate, heptenophos, imicyaphos, isofenphos, isopropyl O-(methoxyaminothio-phosphoryl) salicylate, isoxation, malathion, mecarbam, methamidophos, metidation, mevinphos, monooxidecrotophos, naled, omethoton pair ation, parathion-methyl, phentoate, phorate, phosalone, phosmet, phosphamidon, foxim, pirimiphos-methyl, profenophos, propetamphos, prothiophos, pyraclophos, pyridafenthion, quinalphos, sulfotep, tebupyrimthios, temephos, terbufos, triazophos, trichlorfon, vamidothion.(2) GABA-mediated chloride channel antagonists, includes the following active principles: chlordane, endosulfan, etiprol and fipronil.(3) Sodium channel modulators, includes the following active principles: acrinathrin , alletrin, d-cis-trans alletrin, d-trans alletrin, bifentrin, bioalletrin, bioalletrin S-cyclopentenyl, bioresmetrin, cycloprotrin, ciflutrin, beta-cyflutrin, cialothrin, lambda-cialothrin, gamma-cialotrin, cypermethrin, alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin, zeta-cypermethrin, cyfenotrin [(1R)-trans-isomers], deltamethrin, [(EZ)-(1R)-isomers] of empentrin, esfenvalerate, etofenprox, fenpropatrin, fenvalerate , flucitrinate, flumethrin, tau-fluvalinate, halfenprox, imiprotrin, kadetrin, permethrin, [(1R)-trans-isomer] of fenothrin, prallethrin, pyrethrins (pyrethrum), resmethrin, silafluofen, tefluthrin, tetramethrin, [(1R)-isomers] of tetramethrin, tralomethrin and transflutrin and methoxichlor.( 4) Acetylcholine nicotinic receptor (nA-ChR) agonists include the following active principles: (4A) acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam,(4B) nicotine,(4C) sulfoxaflor,( 4D) flupyradifurone,(4E) triflumezopyrim and dichloromezothiaz.(5) Allosteric activators of the nicotinic acetylcholine receptor (nAChR), includes the following active principles: spinetoram and spinosad.(6) Chloride channel activators, includes the following principles active ingredients: abamectin, emamectin benzoate, lepimectin and milbeectin.(7) Juvenile hormone simulators, includes the following active principles: hydroprene, kinoprene, metoprene, fenoxycarb and pyriproxyfen.(8) Miscellany of non-specific inhibitors (multissi) - uncles), includes the following pris active principles: methyl bromide, chloropicrine, sulfuryl fluoride, borax and tartar emetic.(9) Cordotonal Organ Modulators, includes the following active principles: pymetrozine and flonicamid.(10) Mites growth inhibitors, includes. the following active principles: clofentezine, hethiazox, diflovidazin and ethoxazol.(11) Microbial disruptors of insect mesenteric membranes, it includes the following active principles: Bacillus thuringiensis subsp. Israelensis, Bacillus thuringiensis subsp. aizawai, Bacillus thuringiensis subsp. Kurstaki, Bacillus thuringiensis subsp. tenebrionenis, Bt culture proteins (Cry1Ab, Cry1Ac, Cry1Fa, Cry1A.105, Cry2Ab, Vip3A, mCry3A, Cry3Ab, Cry3Bb, Cry34Ab1/Cry35Ab1) and Bacillus sphaericus. (12) Mitochondrial ATP synthase inhibitors, includes the following active principles: tetradifon, propargite, azocyclotin, cyhexatin, fenbutatin oxide and diafentiuron.(13) Uncouplers of oxidative phosphorylation through proton gradient disruption, includes the following principles actives: chlorfenapyr, DNOC and sulfluramid.(14) Nicotinic acetylcholine receptor (nAChR) channel blockers, includes the following active principles:bensultap, cartap hydrochloride, thiocyclam and tiosultap-sodium.(15) Chitin biosynthesis inhibitors, type 0 includes the following active ingredients: bistrifluron, chlorfluazuron, diflubenzuron, flucicloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron, teflubenzuron and triflumuron.(16) Chitin biosynthesis inhibitors, type 1, includes the following active ingredient. : buprofezin.(17) Dipteran molting disruptor, includes the following active principle: cyromazine.(18) Ecdysone receptor agonists, includes the following p active principles: chromafenozide, halofenozide, methoxyfenozide and tebufenozide.(19) Octopamine receptor agonists, includes the following active principle: amitraz. (20) Inhibitors of mitochondrial complex III electron transport, includes the following active principles hydramethylnon, acequinocil and fluacripyrim.(21) Inhibitors of mitochondrial complex I electron transport, including the following active principles: fenazaquin, fenpyroximate, pyrimidifen, pyridaben, tebufenpyrad, tolfenpyrad and rotenone.(22) Voltage-dependent sodium channel blockers. , includes the following active principles: indoxacarb and metaflumizone.(23) Inhibitors of acetyl CoA carboxylase, includes the following active principles: spirodiclofen, spiromesifen and spirotetramat.(24) Inhibitors of mitochondrial complex IV electron transport, includes the following active principles: aluminum phosphide, calcium phosphide, phosphine, zinc phosphide and cyanide.(25) Inhibitors of electron transport s of mitochondrial complex II, includes the following active principles: cyenopyrafen and cyflumetofen. and(28) Ryanodine receptor modulators, including the following active principles: chlorantraniliprole, cyantraniliprol and flubendiamide.

[00033] Os grupos 26 e 27 não são atribuídos nesta versão do esquema de classificação. Adicionalmente, há um Grupo UN que contém princípios ativos de modo de ação desconhecido ou incerto. Esse grupo inclui os seguintes princípios ativos: azadiractin, benzoximato, bifenazato, bromopropilato, quinometionat, criolita, dicofol, piridalil e pirifluquinazon.[00033] Groups 26 and 27 are not assigned in this version of the classification scheme. Additionally, there is a UN Group that contains active principles of unknown or uncertain mode of action. This group includes the following active principles: azadiractin, benzoximate, biphenazate, bromopropylate, quinomethionate, cryolite, dicofol, pyridalyl and pyrifluquinazon.

[00034] O termo "praga" significa um organismo que é prejudicial a humanos ou preocupações humanas (tais como culturas, alimentos, gado, etc.), onde dito organismo é dos Filos Arthropoda, Mollusca ou Nematoda. Exemplos em particular são formigas, afídios, percevejos, besouros, peixinhos-de-prata, lagartas, baratas, grilos, tesourinhas, pulgas, moscas, gafanhotos, larvas de besouros, vespas, abelhas as-sassinas, cigarrinhas, piolhos, locustas, larvas de moscas, ácaros, ma-riposas, nematódeos, Fulgoromorpha, psilídeos, moscas-serra, cocho- nilhas-de-escama, traças, lesmas, caracóis, aranhas, colêmbolos, ma- rias-fedidas, sínfilos, cupins, tripes, carrapatos, marimbondos, aleirodí- deos e salta-martins.[00034] The term "plague" means an organism that is harmful to humans or human concerns (such as crops, food, livestock, etc.), where said organism is from the Phyla Arthropoda, Mollusca or Nematoda. Examples in particular are ants, aphids, bed bugs, beetles, silverfish, caterpillars, cockroaches, crickets, earwigs, fleas, flies, grasshoppers, beetle larvae, wasps, killer bees, leafhoppers, lice, locusts, larvae of flies, mites, moths, nematodes, Fulgoromorpha, psyllids, sawflies, scale scale insects, moths, slugs, snails, spiders, springtails, stinky crabs, symphylls, termites, thrips, ticks , wasps, aleirodídeos and martins.

[00035] Exemplos adicionais são pragas em (1) Subfilos Chelicerata, Myriapoda e Hexapoda.(2) Classes Arachnida, Symphyla e Insecta.(3) Ordem Anoplura. Uma lista não completa de gêneros em particular inclui, mas não está limitada a, Haematopinus spp., Ho- plopleura spp., Linognathus spp., Pediculus spp., Polyplax spp., Sole- nopotes spp. e Neohaematopinis spp. Uma lista não completa de es-pécies em particular inclui, mas não está limitada a,Haematopinus asi- ni, Haematopinus suis, Linognathus setosus, Linognathusovillus, Pedi- culus humanus capitis, Pediculus humanus humanus e Pthirus pubis.(4) Ordem Coleoptera. Uma lista não completa de gêneros em particular inclui, mas não está limitada a, Acanthoscelides spp., Agriotes spp., Anthonomus spp., Apion spp., Apogonia spp., Araecerus spp., Aulacophora spp., Bruchus spp., Cerosterna spp., Cerotoma spp., Ceutorhynchus spp., Chaetocnema spp., Colaspis spp., Ctenice- ra spp., Curculio spp., Cyclocephala spp., Diabrotica spp., Dinoderus spp., Gnathocerus spp., Hemicoelus spp., Heterobostruchus spp., Hypera spp., Ips spp., Lyctus spp., Megascelis spp., Meligethes spp., Mezium spp., Niptus spp., Otiorhynchus spp., Pantomorus spp., Phyllophaga spp., Phyllotreta spp., Ptinus spp., Rhizotrogus spp., Rhynchites spp., Rhynchophorus spp., Scolytus spp., Sphenophorus spp., Sitophilus spp., Tenebrio spp. e Tribolium spp. Uma lista não completa de espécies particulares inclui, mas não está limitada a, Acanthoscelides obtectus, Agrilus planipennis, Ahasverus advena, Al- phitobius diaperinus, Anoplophora glabripennis, Anthonomus grandis, Anthrenus verbasci, Anthrenus falvipes, Ataenius spretulus, Atomaria linearis, Attagenus unicolor, Bothynoderes punctiventris, Bruchus piso- rum, Callosobruchus maculatus, Carpophilus hemipterus, Cassida vit- tata, Cathartus quadricollis, Cerotoma trifurcata, Ceutorhynchus assi- milis, Ceutorhynchus napi, Conoderus scalaris, Conoderus stigmosus, Conotrachelus nenuphar, Cotinis nitida, Crioceris asparagi, Cryptoles- tes ferrugineus, Cryptolestes pusillus, Cryptolestes turcicus, Cylindro- copturus adspersus, Deporaus marginatus, Dermestes lardarius, Der- mestes maculatus, Epilachna varivestis, Euvrilletta peltata, Faustinus cubae, Hylobius pales, Hylotrupes bajulus, Hypera postica, Hypothe- nemus hampei, Lasioderma serricorne, Leptinotarsa decemlineata, Li- monius canus, Liogenys fuscus, Liogenys suturalis, Lissorhoptrus ory- zophilus, Lophocateres pusillus, Lyctus planicollis, Maecolaspis joliveti, Melanotus communis, Meligethes aeneus, Melolontha melolontha, Ne- crobia rufipes, Oberea brevis, Oberea linearis, Oryctes rhinoceros, Oryzaephilus mercator, Oryzaephilus surinamensis, Oulema melano- pus, Oulema oryzae, Phyllophaga cuyabana, Polycaon stoutti, Popillia japonica, Prostephanus truncatus, Rhyzopertha dominica, Sitona line- atus, Sitophilus granarius, Sitophilus oryzae, Sitophilus zeamais, Ste- gobium paniceum, Tenebroides mauritanicus, Tribolium castaneum, Tribolium confusum, Trogoderma granarium, Trogoderma variabile, Xestobium rufovillosum, e Zabrus tenebrioides.(5) Ordem Dermaptera. Uma lista não completa de espé-cies em particular inclui, mas não está limitada a, Forficula auricularia.(6) Ordem Blattaria. Uma lista não completa de espécies em particular inclui, mas não está limitada a, Blattella germanica, Blat- tella asahinai, Blatta orientalis, Blatta lateralis, Parcoblatta pennsylva- nica, Periplaneta americana, Periplaneta australasiae, Periplaneta bru- nnea, Periplaneta fuliginosa, Pycnoscelus surinamensis e Supella lon- gipalpa.(7) Ordem Diptera. Uma lista não completa de gêneros em particular inclui, mas não está limitada a, Aedes spp., Agromyza spp., Anastrepha spp., Anopheles spp., Bactrocera spp., Ceratitis spp., Chrysops spp., Cochliomyia spp., Contarinia spp., Culex spp., Culicoi- des spp., Dasineura spp., Delia spp., Drosophila spp., Fannia spp., Hylemya spp., Liriomyza spp., Musca spp., Phorbia spp., Pollenia spp., Psychoda spp., Simulium spp., Tabanus spp. e Tipula spp. Uma lista não completa de espécies em particular inclui, mas não está limitada a, Agromyza frontella, Anastrepha suspensa, Anastrepha ludens, Anastrepha obliqua, Bactrocera cucurbitae, Bactrocera dorsalis, Bac- trocera invadens, Bactrocera zonata, Ceratitis capitata, Dasineura brassicae, Delia platura, Fannia canicularis, Fannia scalaris, Gaste- rophilus intestinalis, Gracillia perseae, Haematobia irritans, Hypoderma lineatum, Liriomyza brassicae, Melophagus ovinus, Musca autumnalis, Musca domestica, Oestrus ovis, Oscinella frit, Pegomya betae, Piophi- la casei, Psila rosae, Rhagoletis cerasi, Rhagoletis pomonella, Rhago- letis mendax, Sitodiplosis mosellana e Stomoxys calcitrans.(8) Ordem Hemiptera. Uma lista não completa de gêneros em particular inclui, mas não está limitada a, Adelges spp., Aula- caspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Ceroplastes spp., Chionaspis spp., Chrysomphalus spp., Coccus spp., Empoasca spp., Euschistus spp., Lepidosaphes spp., Lagynotomus spp., Lygus spp., Macrosiphum spp., Nephotettix spp., Nezara spp., Nilaparvata spp., Philaenus spp., Phytocoris spp., Piezodorus spp., Planococcus spp., Pseudococcus spp., Rhopalosiphum spp., Saissetia spp., Therio- aphis spp., Toumeyella spp., Toxoptera spp., Trialeurodes spp., Tria- toma spp. e Unaspis spp. Uma lista não completa de espécies particulares inclui, mas não está limitada a, Acrosternum hilare, Acyrtho- siphon pisum, Aleyrodes proletella, Aleurodicus dispersus, Aleurothri- xus floccosus, Amrasca biguttula biguttula, Aonidiella aurantii, Aphis gossypii, Aphis glycines, Aphis pomi, Aulacorthum solani, Bactericera cockerelli, Bagrada hilaris, Bemisia argentifolii, Bemisia tabaci, Blissus leucopterus, Boisea trivittata, Brachycorynella asparagi, Brevennia re- hi, Brevicoryne brassicae, Cacopsylla pyri, Cacopsylla pyricola, Calo- coris norvegicus, Ceroplastes rubens, Cimex hemipterus, Cimex lectu- larius, Dagbertus fasciatus, Dichelops furcatus, Diuraphis noxia, Dia- phorina citri, Dysaphis plantaginea, Dysdercus suturellus, Edessa me-ditabunda, Eriosoma lanigerum, Eurygaster maura, Euschistus cons- persus, Euschistus heros, Euschistus servus, Halyomorpha halys, He- lopeltis antonii, Helopeltis theivora, Icerya purchasi, Idioscopus nitidu- lus, Laodelphax striatellus, Leptocorisa oratorius, Leptocorisa varicor- nis, Lygus hesperus, Maconellicoccus hirsutus, Macrosiphum euphor- biae, Macrosiphum granarium, Macrosiphum rosae, Macrosteles qua- drilineatus, Mahanarva frimbiolata, Megacopta cribraria, Metopo- lophium dirhodum, Mictis longicornis, Myzus persicae, Nephotettix cincticeps, Neurocolpus longirostris, Nezara viridula, Nilaparvata lu- gens, Parlatoria pergandii, Parlatoria ziziphi, Peregrinus maidis, Phylloxera vitifoliae, Physokermes piceae, Phytocoris californicus, Phytocoris relativus, Piezodorus guildinii, Poecilocapsus lineatus, Psallus vaccinicola, Pseudacysta perseae, Pseudococcus brevipes, Quadraspidiotus perniciosus, Rhopalosiphum maidis, Rhopalosiphum padi, Saissetia oleae, Scaptocoris castanea, Schizaphis graminum, Sitobion avenae, Sogatella furcifera, Trialeurodes vaporariorum, Tria- leurodes abutiloneus, Unaspis yanonensis, e Zulia entrerriana.(9) Ordem Hymenoptera. Uma lista não completa de gêne-ros em particular inclui, mas não está limitada a, Acromyrmex spp., Atta spp., Camponotus spp., Diprion spp., Dolichovespula spp., Formica spp., Monomorium spp., Neodiprion spp., Paratrechina spp., Pheidole spp., Pogonomyrmex spp., Polistes spp., Solenopsis spp., Technomyrmex, spp., Tetramorium spp., Vespula spp., Vespa spp. e Xylocopa spp. Uma lista não completa de espécies em particular inclui, mas não está limitada a, Athalia rosae, Atta texana, Caliroa cerasi, Cimbex americana, Iri- domyrmex humilis, Linepithema humile, Mellifera Scutellata, Monomorium minimum, Monomorium pharaonis, Neodiprion sertifer, Solenopsis invicta, Solenopsis geminata, Solenopsis molesta, Solenopsis richtery, Sole- nopsis xyloni, Tapinoma sessile e Wasmannia auropunctata. (10) Ordem Isoptera. Uma lista não completa de gêneros em particular inclui, mas não está limitada a, Coptotermes spp., Corni- termes spp., Cryptotermes spp., Heterotermes spp., Kalotermes spp., Incisitermes spp., Macrotermes spp., Marginitermes spp., Microcero- termes spp., Procornitermes spp., Reticulitermes spp., Schedorhino- termes spp. e Zootermopsis spp. Uma lista não completa de espécies em particular inclui, mas não está limitada a, Coptotermes acinacifor- mis, Coptotermes curvignathus, Coptotermes frenchi, Coptotermes formosanus, Coptotermes gestroi, Cryptotermes brevis, Heterotermes aureus, Heterotermes tenuis, Incisitermes minor, Incisitermes snyderi, Microtermes obesi, Nasutitermes corniger, Odontotermes formosanus, Odontotermes obesus, Reticulitermes banyulensis, Reticulitermes grassei, Reticulitermes flavipes, Reticulitermes hageni, Reticulitermes hesperus, Reticulitermes santonensis, Reticulitermes speratus, Reticu- litermes tibialis e Reticulitermes virginicus.(11) Ordem Lepidoptera. Uma lista não completa de gêneros em particular inclui, mas não está limitada a, Adoxophyes spp., Agrotis spp., Argyrotaenia spp., Cacoecia spp., Caloptilia spp., Chilo spp., Chrysodeixis spp., Colias spp., Crambus spp., Diaphania spp., Diatraea spp., Earias spp., Ephestia spp., Epimecis spp., Feltia spp., Gortyna spp., Helicoverpa spp., Heliothis spp., Indarbela spp., Litho- colletis spp., Loxagrotis spp., Malacosoma spp., Nemapogon spp., Pe- ridroma spp., Phyllonorycter spp., Pseudaletia spp., Plutella spp., Se- samia spp., Spodoptera spp., Synanthedon spp. e Yponomeuta spp. Uma lista não completa de espécies particulares inclui, mas não está limitada a, Achaea janata, Adoxophyes orana, Agrotis ipsilon, Alabama argillacea, Amorbia cuneana, Amyelois transitella, Anacamptodes defectaria, Anarsia lineatella, Anomis sabulifera, Anticarsia gemmatalis, Archips argyrospila, Archips rosana, Argyrotaenia citrana, Autographa gamma, Bonagota cranaodes, Borbo cinnara, Bucculatrix thurberiella, Capua reticulana, Carposina niponensis, Chlumetia transversa, Choris- toneura rosaceana, Cnaphalocrocis medinalis, Conopomorpha crame- rella, Corcyra cephalonica, Cossus cossus, Cydia caryana, Cydia fu- nebrana, Cydia molesta, Cydia nigricana, Cydia pomonella, Darna di- ducta, Diaphania nitidalis, Diatraea saccharalis, Diatraea grandiosella, Earias insulana, Earias vittella, Ecdytolopha aurantianum, Elasmopal- pus lignosellus, Ephestia cautella, Ephestia elutella, Ephestia kuehniel- la, Epinotia aporema, Epiphyas postvittana, Erionota thrax, Estigmene acrea, Eupoecilia ambiguella, Euxoa auxiliaris, Galleria mellonella, Grapholita molesta, Hedylepta indicata, Helicoverpa armigera, Helico- verpa zea, Heliothis virescens, Hellula undalis, Keiferia lycopersicella, Leucinodes orbonalis, Leucoptera coffeella, Leucoptera malifoliella, Lobesia botrana, Loxagrotis albicosta, Lymantria dispar, Lyonetia cler- kella, Mahasena corbetti, Mamestra brassicae, Manduca sexta, Maru- ca testulalis, Metisa plana, Mythimna unipuncta, Neoleucinodes ele- gantalis, Nymphula depunctalis, Operophtera brumata, Ostrinia nubila- lis, Oxydia vesulia, Pandemis cerasana, Pandemis heparana, Papilio demodocus, Pectinophora gossypiella, Peridroma saucia, Perileucop- tera coffeella, Phthorimaea operculella, Phyllocnistis citrella, Phyllo- norycter blancardella, Pieris rapae, Plathypena scabra, Platynota idaeusalis, Plodia interpunctella, Plutella xylostella, Polychrosis vitea- na, Prays endocarpa, Prays oleae, Pseudaletia unipuncta, Pseudoplu- sia includens, Rachiplusia nu, Scirpophaga incertulas, Sesamia inferens, Sesamia nonagrioides, Setora nitens, Sitotroga cerealella, Spar- ganothis pilleriana, Spodoptera exigua, Spodoptera frugiperda, Spodoptera eridania, Thecla basilides, Tinea pellionella, Tineola bissel- liella, Trichoplusia ni, Tuta absoluta, Zeuzera coffeae, e Zeuzea pyrina.(12) Ordem Mallophaga. Uma lista não completa de gêneros em particular inclui, mas não está limitada a, Anaticola spp., Bo- vicola spp., Chelopistes spp., Goniodes spp., Menacanthus spp. e Tri- chodectes spp. Uma lista não completa de espécies em particular inclui, mas não está limitada a, Bovicola bovis, Bovicola caprae, Bovicola ovis, Chelopistes meleagridis, Goniodes dissimilis, Goniodes gigas, Menacanthus stramineus, Menopon gallinae e Trichodectes canis.(13) Ordem Orthoptera. Uma lista não completa de gêneros em particular inclui, mas não está limitada a, Melanoplus spp. e Pterophylla spp. Uma lista não completa de espécies em particular inclui, mas não está limitada a, Acheta domesticus, Anabrus simplex, Gryllotalpa africana, Gryllotalpa australis, Gryllotalpa brachyptera, Gryllotalpa hexadactyla, Locusta migratoria, Microcentrum retinerve, Schistocerca gregaria e Scudderia furcata.(14) Ordem Psocoptera. Uma lista não completa de espécies em particular inclui, mas não está limitada a, Liposcelis decolor, Liposcelis entomophila, Lachesilla quercus e Trogium pulsatorium.(15) Ordem Siphonaptera. Uma lista não completa de espécies em particular inclui, mas não está limitada a, Ceratophyllus gallinae, Ceratophyllus niger, Ctenocephalides canis, Ctenocephalides felis e Pulex irritans.(16) Ordem Thysanoptera. Uma lista não completa de gêneros em particular inclui, mas não está limitada a, Caliothrips spp., Frankliniella spp., Scirtothrips spp. e Thrips spp. Uma lista não completa de espécies em particular inclui, mas não está limitada a, Franklini- ella bispinosa, Frankliniella fusca, Frankliniella occidentalis, Frankliniel- la schultzei, Frankliniella tritici, Frankliniella williamsi, Heliothrips hae- morrhoidalis, Rhipiphorothrips cruentatus, Scirtothrips citri, Scirtothrips dorsalis, Taeniothrips rhopalantennalis, Thrips hawaiiensis, Thrips ni- gropilosus, Thrips orientalis, Thrips palmi e Thrips tabaci.(17) Ordem Thysanura. Uma lista não completa de gêneros em particular inclui, mas não está limitada a, Lepisma spp. e Thermobia spp. (18) Ordem Acarina. Uma lista não completa de gêneros em particular inclui, mas não está limitada a, Acarus spp., Aculops spp., Argus spp., Boophilus spp., Demodex spp., Dermacentor spp., Epitrimerus spp., Eriophyes spp., Ixodes spp., Oligonychus spp., Pa- nonychus spp., Rhizoglyphus spp. e Tetranychus spp. Uma lista não completa de espécies em particular inclui, mas não está limitada a, Acarapis woodi, Acarus siro, Aceria mangiferae, Aculops lycopersici, Aculus pelekassi, Aculus schlechtendali, Amblyomma americanum, Brevipalpus obovatus, Brevipalpus phoenicis, Dermacentor variabilis, Dermatophagoides pteronyssinus, Eotetranychus carpini, Liponyssoi- des sanguineus, Notoedres cati, Oligonychus coffeae, Oligonychus ili- cis, Ornithonyssus bacoti, Panonychus citri, Panonychus ulmi, Phyllo- coptruta oleivora, Polyphagotarsonemus latus, Rhipicephalus sanguineus, Sarcoptes scabiei, Tegolophus perseaflorae, Tetranychus urti- cae, Tyrophagus longior e Varroa destructor.(19) Ordem Araneae. Uma lista não completa de gêneros em particular inclui, mas não está limitada a,Loxosceles spp.Latrodectus spp., and Atrax spp. Uma lista não completa de espécies em particular inclui, mas não está limitada a, Loxosceles reclusa, Latrodectus mactans e Atrax robustus.(20) Classe Symphyla. Uma lista não completa de espécies em particular inclui, mas não está limitada a, Scutigerella immaculata.(21) Subclasse Collembola. Uma lista não completa de espécies em particular inclui, mas não está limitada a, Bourletiella hor- tensis, Onychiurus armatus, Onychiurus fimetarius e Sminthurus viridis.(22) Filo Nematoda. Uma lista não completa de gêneros em particular inclui, mas não está limitada a, Aphelenchoides spp., Belo- nolaimus spp., Criconemella spp., Ditylenchus spp., Globodera spp., He-terodera spp., Hirschmanniella spp., Hoplolaimus spp., Meloidogyne spp., Pratylenchus spp. e Radopholus spp. Uma lista não completa de espé- cies em particular inclui, mas não está limitada a, Dirofilaria immitis, Glo- bodera pallida, Heterodera glycines, Heterodera zeae, Meloidogyne in-cognita, Meloidogyne javanica, Onchocerca volvulus, Pratylenchus pene-trans, Radopholus similis e Rotylenchulus reniformis.(23) Filo Mollusca. Uma lista não completa de espécies em particular inclui, mas não está limitada a, Arion vulgaris, Cornu as- persum, Deroceras reticulatum, Limax flavus, Milax gagates e Poma- cea canaliculata.[00035] Additional examples are pests in (1) Subphyla Chelicerata, Myriapoda and Hexapoda.(2) Classes Arachnida, Symphyla and Insecta.(3) Order Anoplura. An incomplete list of particular genera includes, but is not limited to, Haematopinus spp., Hoplopleura spp., Linognathus spp., Pediculus spp., Polyplax spp., Solenopotes spp. and Neohaematopinis spp. An incomplete list of particular species includes, but is not limited to, Haematopinus asini, Haematopinus suis, Linognathus setosus, Linognathusovillus, Pediculus humanus capitis, Pediculus humanus humanus, and Pthirus pubis.(4) Order Coleoptera. An incomplete list of particular genera includes, but is not limited to, Acanthoscelides spp., Agriotes spp., Anthonomus spp., Apion spp., Apogonia spp., Araecerus spp., Aulacophora spp., Bruchus spp., Cerosterna spp. ., Cerotoma spp., Ceutorhynchus spp., Chaetocnema spp., Colaspis spp., Ctenicera spp., Curculio spp., Cyclocephala spp., Diabrotica spp., Dinoderus spp. ., Hypera spp., Ips spp., Lyctus spp., Megascelis spp., Meligethes spp., Mezium spp., Niptus spp., Otiorhynchus spp., Pantomorus spp., Phyllophaga spp., Phyllophaga spp., Phyllophaga spp., Phyllophaga spp. Rhizotrogus spp., Rhynchites spp., Rhynchophorus spp., Scolytus spp., Sphenophorus spp., Sitophilus spp., Tenebrio spp. and Tribolium spp. An incomplete list of particular species includes, but is not limited to, Acanthoscelides obtectus, Agrilus planipennis, Ahasverus advena, Alphitobius diaperinus, Anoplophora glabripennis, Anthonomus grandis, Anthrenus verbasci, Anthrenus falvipesaria, Ataenius linearis, Ataenius spretu Bothynoderes punctiventris, Bruchus pisorum, Callosobruchus maculatus, Carpophilus hemipterus, Cassida vittata, Cathartus quadricollis, Cerotoma trifurcata, Ceutorhynchus assimilis, Ceutorhynchus napi, Conoderus scalaris, Condo- ni- s- scalaris, Crimostinis, Conoderus s- tes ferrugineus, Cryptolestes pusillus, Cryptolestes turcicus, Cylindrocopturus adspersus, Deporaus marginatus, Dermestes lardarius, Dermestes maculatus, Epilachna varivestis, Euvrilletta peltata, Faustinus cubae, Hylobius- pe- seri- pesico, Ladarius, Hyperpotrupesio , Leptinotarsa decemlineata, Limonius canus, Li ogenys fuscus, Liogenys suturalis, Lissorhoptrus oryzophilus, Lophocateres pusillus, Lyctus planicollis, Maecolaspis joliveti, Melanotus communis, Meligethes aeneus, Melolontha melolontha, Necrobia rufipes, Oberea philaryis, Oberea philaryis, Oberea philulyza, Oberea philaryis, Oberrea melanopus, Oulema oryzae, Phyllophaga cuyabana, Polycaon stoutti, Popillia japonica, Prostephanus truncatus, Rhyzopertha dominica, Sitona lineatus, Sitophilus granarius, Sitophilus oryzae, Sitophilus zeamais, Ste- gobium panicium, Tribolus, Tribolus panicium Trogoderma granarium, Trogoderma variabile, Xestobium rufovillosum, and Zabrus tenebrioides.(5) Order Dermaptera. An incomplete list of particular species includes, but is not limited to, Forficula auricularia. (6) Order Blattaria. An incomplete list of particular species includes, but is not limited to, Blattella germanica, Blattella asahinai, Blatta orientalis, Blatta lateralis, Parcoblatta pennsylvanica, Periplaneta americana, Periplaneta australasiae, Periplaneta brunnea, Periplaneta fuliginosa, Pycnoscelus surinamensis and Supella longipalpa.(7) Order Diptera. An incomplete list of particular genera includes, but is not limited to, Aedes spp., Agromyza spp., Anastrepha spp., Anopheles spp., Bactrocera spp., Ceratitis spp., Chrysops spp., Cochliomyia spp., Contarinia spp. ., Culex spp., Culicoides spp., Dasineura spp., Delia spp., Drosophila spp., Fannia spp., Hylemya spp., Liriomyza spp., Musca spp., Phorbia spp., Pollenia spp., Psychoda spp. ., Simulium spp., Tabanus spp. and Tipula spp. An incomplete list of particular species includes, but is not limited to, Agromyza frontella, Anastrepha suspended, Anastrepha ludens, Anastrepha obliqua, Bactrocera cucurbitae, Bactrocera dorsalis, Bactrocera invadens, Bactrocera zonata, Ceratitis capitata, Dasineura brassicae, Delia platura , Fannia canicularis, Fannia scalaris, Gasterophilus intestinalis, Gracillia perseae, Haematobia irritans, Hypoderma lineatum, Liriomyza brassicae, Melophagus ovinus, Musca autumnalis, Musca domestica, Oestrus ovis, Oscinella frit, Pegomya rosae, Piophisilae, Piophisilae Rhagoletis cerasi, Rhagoletis pomonella, Rhagoletis mendax, Sitodiplosis mosellana and Stomoxys calcitrans.(8) Order Hemiptera. An incomplete list of particular genera includes, but is not limited to, Adelges spp., Aula-caspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Ceroplastes spp., Chionaspis spp., Chrysomphalus spp., Coccus spp., Empoasca spp., Euschistus spp., Lepidosaphes spp., Lagynotomus spp., Lygus spp., Macrosiphum spp., Nephotettix spp., Nezara spp., Nilaparvata spp., Piezotomus spp., Philzous spp. ., Planococcus spp., Pseudococcus spp., Rhopalosiphum spp., Saissetia spp., Therio-aphis spp., Toumeyella spp., Toxoptera spp., Trialeurodes spp., Tria- toma spp. and Unaspis spp. An incomplete list of particular species includes, but is not limited to, Acrosternum hilare, Acyrthosiphon pisum, Aleyrodes proletella, Aleurodicus dispersus, Aleurothrixus floccosus, Amrasca biguttula biguttula, Aonidiella aurantii, Aphis gossypii, Aphis poglycines Aulacorthum solani, Bactericera cockerelli, Bagrada hilaris, Bemisia argentifolii, Bemisia tabaci, Blissus leucopterus, Boisea trivittata, Brachycorynella asparagi, Brevennia re-hi, Brevicoryne brassicae, Cacopsylla pyri, Cacopsylla pyri, Cacopsylla pyri, Cacopsymexus hemexus, normexus, norm. lectularius, Dagbertus fasciatus, Dichelops furcatus, Diuraphis noxia, Diaphorina citri, Dysaphis plantaginea, Dysdercus suturellus, Edessa me-ditabunda, Eriosoma lanigerum, Eurygaster maura, Euschistus cons- persus, Euschistus heromorphs, Euschistus seramorphs - lopeltis antonii, Helopeltis theivora, Icerya purchasi, Idioscopus nitidulus, Laodelphax striatellus, Leptocorisa o ratrius, Leptocorisa varicornis, Lygus hesperus, Maconellicoccus hirsutus, Macrosiphum euphorbiae, Macrosiphum granarium, Macrosiphum rosae, Macrosteles quadrilineatus, Mahanarva frimbiolata, Macrocopta cribraria, Megacopta Mypus- phi- sic- epti- siclo longirostris, Nezara viridula, Nilaparvata lugens, Parlatoria pergandii, Parlatoria ziziphi, Peregrinus maidis, Phylloxera vitifoliae, Physokermes piceae, Phytocoris californicus, Phytocoris relativus, Piezodorus guildlusses ziziphi, Peregrinus maidis, Patus maidis, Rhopalosiphum padi, Saissetia oleae, Scaptocoris castanea, Schizaphis graminum, Sitobion avenae, Sogatella furcifera, Trialeurodes vaporariorum, Trialeurodes abutiloneus, Unaspis yanonensis, and Zulia entrerriana.(9) Order Hymenoptera. An incomplete list of particular genera includes, but is not limited to, Acromyrmex spp., Atta spp., Camponotus spp., Diprion spp., Dolichovespula spp., Formica spp., Monomorium spp., Neodiprion spp., Paratrechina spp., Pheidole spp., Pogonomyrmex spp., Polistes spp., Solenopsis spp., Technomyrmex spp., Tetramorium spp., Vespula spp., Vespa spp. and Xylocopa spp. An incomplete list of particular species includes, but is not limited to, Athalia rosae, Atta texana, Caliroa cerasi, Cymbex americana, Iridomyrmex humilis, Linepithema humile, Mellifera Scutellata, Monomorium minimum, Monomorium pharaonis, Neodiprion sertifer, Solenopsis invicta , Solenopsis geminata, Solenopsis molesta, Solenopsis richtery, Solenopsis xyloni, Tapinoma sessile and Wasmannia auropunctata. (10) Isoptera Order. An incomplete list of particular genera includes, but is not limited to, Coptotermes spp., Cornitermes spp., Cryptotermes spp., Heterotermes spp., Kalotermes spp., Incisitermes spp., Macrotermes spp., Marginitermes spp., Microcerotermes spp., Procornitermes spp., Reticulitermes spp., Schedorhinotermes spp. and Zoothermopsis spp. An incomplete list of particular species includes, but is not limited to, Coptotermes acinaciformis, Coptotermes curvignathus, Coptotermes frenchi, Coptotermes formosanus, Coptotermes gestroi, Cryptotermes brevis, Heterotermes aureus, Heterotermes tenuis, Incisitermes, Incisitermes , Nasutitermes corniger, Odontotermes formosanus, Odontotermes obesus, Reticulitermes banyulensis, Reticulitermes grassei, Reticulitermes flavipes, Reticulitermes hageni, Reticulitermes hesperus, Reticulitermes santonensis(1, Reticulitermes sperticlitermes-atus. An incomplete list of particular genera includes, but is not limited to, Adoxophyes spp., Agrotis spp., Argyrotaenia spp., Cacoecia spp., Caloptilia spp., Chilo spp., Chrysodeixis spp., Colias spp., Crambus spp. ., Diaphania spp., Diatraea spp., Earias spp., Ephestia spp., Epimecis spp., Feltia spp., Gortyna spp., Helicoverpa spp., Heliothis spp., Indarbela spp. ., Malacosoma spp., Nemapogon spp., Peridroma spp., Phyllonorycter spp., Pseudaletia spp., Plutella spp., Sesamia spp., Spodoptera spp., Synanthedon spp. and Yponomeuta spp. An incomplete list of particular species includes, but is not limited to, Achaea janata, Adoxophyes orana, Agrotis ipsilon, Alabama argillacea, Amorbia cuneana, Amyelois transitella, Anacamptodes defectaria, Anarsia lineatella, Anomis sabulifera, Anticarsia gemmatalis, Archips argyrospila, Archips rosana , Argyrotaenia citrana, Autographa gamma, Bonagota cranaodes, Borbo cinnara, Bucculatrix thurberiella, Capua reticulana, Carposina niponensis, Chlumetia transversa, Choristoneura rosacean, Cnaphalocrocis medinalis, Copomorpha crame- rella, Cydia- cephalo nebrana, Cydia molesta, Cydia nigricana, Cydia pomonella, Darna diducta, Diaphania nitidalis, Diatraea saccharalis, Diatraea grandiosella, Earias insulana, Earias vittella, Ecdytolopha aurantianum, Elasmopalpus lignosellus, Ephestia cautia, Ephestia cautia Epinotia aporema, Epiphyas postvittana, Erionota thrax, Stigmene acrea, Eupoecilia ambiguell a, Euxoa auxiliaryis, Galleria mellonella, Grapholita molesta, Hedylepta indicata, Helicoverpa armigera, Helicoverpa zea, Heliothis virescens, Hellula undalis, Keiferia lycopersicella, Leucinodes orbonalis, Leucoptera coffeella, Leucoptera, Lobes malifoliana, Lyucoptera, Lobes malifoliana clerkella, Mahasena corbetti, Mamestra brassicae, Manduca sexta, Maruca testulalis, Metisa plana, Mythimna unipuncta, Neoleucinodes elegantalis, Nymphula depunctalis, Operophtera brumata, Ostrinia nubilalis, Oxydia vesulia, Pandemis he- rasa demodocus, Pectinophora gossypiella, Peridroma saucia, Perileucoptera coffeella, Phthorimaea operculella, Phyllocnistis citrella, Phyllonorycter blancardella, Pieris rapae, Plathypena scabra, Platynota idaeusalis, Platynota idaeusalis, Plodia and Plodia interpunctella interpunctella Pseudaletia unipuncta, Pseudoplusia includens, Rachiplusia nu, Scirpophaga incertula s, Sesamia inferens, Sesamia nonagrioides, Setora nitens, Sitotroga cerealella, Sparganothis pilleriana, Spodoptera exigua, Spodoptera frugiperda, Spodoptera eridania, Thecla basilides, Tinea pellionella, Tineola bissel-liella, Zeera cozuzae, Zeeracoplusia s. pyrina.(12) Order Mallophaga. An incomplete list of particular genera includes, but is not limited to, Anaticola spp., Bovicola spp., Chelopistes spp., Goniodes spp., Menacanthus spp. and Trichodectes spp. An incomplete list of particular species includes, but is not limited to, Bovicola bovis, Bovicola caprae, Bovicola ovis, Chelopistes meleagridis, Goniodes dissimilis, Goniodes gigas, Menacanthus stramineus, Menopon gallinae, and Trichodectes canis.(13) Order Orthoptera. An incomplete list of particular genera includes, but is not limited to, Melanoplus spp. and Pterophylla spp. An incomplete list of particular species includes, but is not limited to, Acheta domesticus, Anabrus simplex, Gryllotalpa africana, Gryllotalpa australis, Gryllotalpa brachyptera, Gryllotalpa hexadactyla, Locusta migratoria, Microcentrum retinerve, Schistocerca gregaria and Scudderia furcata(14) Order. Psocopter. An incomplete list of particular species includes, but is not limited to, Liposcelis decolor, Liposcelis entomophila, Lachesilla quercus, and Trogium pulsatorium.(15) Order Siphonaptera. An incomplete list of particular species includes, but is not limited to, Ceratophyllus gallinae, Ceratophyllus niger, Ctenocephalides canis, Ctenocephalides felis, and Pulex irritans.(16) Order Thysanoptera. An incomplete list of particular genera includes, but is not limited to, Caliothrips spp., Frankliniella spp., Scirtothrips spp. and Thrips spp. An incomplete list of particular species includes, but is not limited to, Frankliniella bispinosa, Frankliniella fusca, Frankliniella occidentalis, Frankliniella schultzei, Frankliniella tritici, Frankliniella williamsi, Heliothrips haemorrhoidalis, Rhipiphorothrips cruentatus, Scirtothrips cirtothrips dorsalis, Taeniothrips rhopalantennalis, Thrips hawaiiensis, Thrips nigropilosus, Thrips orientalis, Thrips palmi and Thrips tabaci.(17) Order Thysanura. An incomplete list of particular genera includes, but is not limited to, Lepisma spp. and Thermobia spp. (18) Order Acarina. An incomplete list of particular genera includes, but is not limited to, Acarus spp., Aculops spp., Argus spp., Boophilus spp., Demodex spp., Dermacentor spp., Epitrimerus spp., Eriophyes spp., Ixodes spp. ., Oligonychus spp., Panonychus spp., Rhizoglyphus spp. and Tetranychus spp. An incomplete list of particular species includes, but is not limited to, Acarapis woodi, Acarus siro, Aceria mangiferae, Aculops lycopersici, Aculus pelekassi, Aculus schlechtendali, Amblyomma americanum, Brevipalpus obovatus, Brevipalpus phoenicisides, Ermacentor variates carpini, Liponyssoides sanguineus, Notoedres cati, Oligonychus coffeae, Oligonychus ilicis, Ornithonyssus bacoti, Panonychus citri, Panonychus ulmi, Phyllocoptrout oleivora, Polyphagotarsonemus ilicis, Polyphagotarsonemus sancera, Rh. longior and Varroa destructor.(19) Order Araneae. An incomplete list of particular genera includes, but is not limited to, Loxosceles spp.Latrodectus spp., and Atrax spp. An incomplete list of particular species includes, but is not limited to, Loxosceles reclusa, Latrodectus mactans and Atrax robustus. (20) Class Symphyla. An incomplete list of particular species includes, but is not limited to, Scutigerella immaculata.(21) Subclass Collembola. An incomplete list of particular species includes, but is not limited to, Bourletiella hortensis, Onychiurus armatus, Onychiurus fimetarius, and Sminthurus viridis.(22) Phylum Nematoda. An incomplete list of particular genera includes, but is not limited to, Aphelenchoides spp., Belonolaimus spp., Criconemella spp., Ditylenchus spp., Globodera spp., Heterodera spp., Hirschmanniella spp., Hoprolaimus spp. ., Meloidogyne spp., Pratylenchus spp. and Radopholus spp. An incomplete list of particular species includes, but is not limited to, Dirofilaria immitis, Globodera pallida, Heterodera glycines, Heterodera zeae, Meloidogyne in-cognita, Meloidogyne javanica, Onchocerca volvulus, Pratylenchus pene-ilis, Radopholus sim and Rotylenchulus reniformis.(23) Phylum Mollusca. An incomplete list of particular species includes, but is not limited to, Arion vulgaris, Cornu aspersum, Deroceras reticulatum, Limax flavus, Milax gagates, and Pomacea canaliculata.

[00036] Um grupo de pragas particularmente preferencial para controle é de pragas mastigadoras. Pragas mastigadoras em geral têm aparelhos bucais perfurantes e/ou sugadores e se alimentam da seiva e tecidos vegetais internos de plantas. Exemplos de pragas que se alimentam de seiva de interesse em particular para a agricultura incluem, mas não estão limitados a, afídios, cigarrinhas, mariposas, cocho- nilhas-de-escama, tripes, psilídeos, cochonilhas-farinhentas, marias- fedidas e aleirodídeos. Exemplos específicos de Ordens que tenham pragas que se alimentam de seiva de interesse na agricultura incluem, mas não estão limitados a, Anoplura e Hemiptera. Exemplos específicos de Hemiptera, que são de interesse na agricultura incluem, mas não estão limitados a, Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Coccus spp., Euschistus spp., Lygus spp., Macrosiphum spp., Nezara spp. e Rhopalosiphum spp.[00036] A particularly preferred group of pests for control is chewing pests. Chewing pests generally have perforating and/or sucking mouthparts and feed on the sap and internal plant tissues of plants. Examples of sap-feeding pests of particular interest to agriculture include, but are not limited to, aphids, leafhoppers, moths, scale scale insects, thrips, psyllids, mealy scale insects, stink beetles, and aleroids . Specific examples of Orders that have sap feeding pests of interest in agriculture include, but are not limited to, Anoplura and Hemiptera. Specific examples of Hemiptera, which are of interest in agriculture include, but are not limited to, Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Coccus spp., Euschistus spp., Lygus spp., Macrosiphum spp. , Nezara spp. and Rhopalosiphum spp.

[00037] Outro grupo de pragas particularmente preferencial para controlar é pragas mastigadoras. Pragas mastigadoras em geral têm um aparelho bucal que lhes permite mastigar tecidos vegetais, incluindo raízes, caules, folhas, botões e tecidos reprodutores (incluindo, mas não limitados a, flores, frutos e sementes). Exemplos de pragas mastigado- ras de interesse particular na agricultura incluem, mas não estão limita-dos a, lagartas, besouros, gafanhotos e locustas. Exemplos específicos de Ordens que tenham pragas mastigadoras de interesse na agri- cultura incluem, mas não estão limitados a, Coleoptera e Lepidoptera. Exemplos específicos de Coleoptera que são de interesse na agricultura incluem, mas não estão limitados a, Anthonomus spp., Cerotoma spp., Chaetocnema spp., Colaspis spp., Cyclocephala spp., Diabrotica spp., Hypera spp., Phyllophaga spp., Phyllotreta spp., Sphenophorus spp., Sitophilus spp.[00037] Another group of pests particularly preferred to control is chewing pests. Chewing pests generally have a mouthpart that allows them to chew plant tissue, including roots, stems, leaves, buds and reproductive tissues (including, but not limited to, flowers, fruits and seeds). Examples of chewing pests of particular interest in agriculture include, but are not limited to, caterpillars, beetles, locusts and locusts. Specific examples of Orders that have chewing pests of interest in agriculture include, but are not limited to, Coleoptera and Lepidoptera. Specific examples of Coleoptera that are of interest in agriculture include, but are not limited to, Anthonomus spp., Cerotoma spp., Chaetocnema spp., Colaspis spp., Cyclocephala spp., Diabrotica spp., Hypera spp., Phyllophaga spp., Phyllotreta spp., Sphenophorus spp., Sitophilus spp.

[00038] A frase "quantidade pesticidamente eficaz" significa a quantidade de um pesticida necessária para atingir um efeito observável em uma praga, por exemplo, os efeitos de necrose, morte, retardamento, prevenção, remoção, destruição ou, de outra forma, diminuição da ocorrência e/ou da atividade de uma praga em um local. Esse efeito pode surgir quando populações de pragas são repelidas de um local, as pragas são incapacitadas em, ou ao redor de, um local, e/ou pragas são exterminadas em, ou ao redor de, um local. Naturalmente, uma combinação desses efeitos pode ocorrer. Geralmente, populações de pragas, atividade ou ambos são desejavelmente reduzidas em mais de cinquenta por cento, preferencialmente mais de 90 por cento, e mais preferencialmente mais de 99 por cento. Em geral, uma quantidade pesticidamente eficaz, para fins agrícolas, é de cerca de 0,0001 grama por hectare a cerca de 5000 gramas por hectare, preferencialmente de cerca de 0,0001 grama por hectare a cerca de 500 gramas por hectare, e é ainda mais preferencialmente de cerca de 0,0001 grama por hectare a cerca de 50 gramas por hectare.[00038] The phrase "pesticide effective amount" means the amount of a pesticide necessary to achieve an observable effect on a pest, for example, the effects of necrosis, death, delay, prevention, removal, destruction or otherwise diminishing occurrence and/or activity of a pest in a location. This effect can arise when pest populations are repelled from a location, pests are disabled in or around a location, and/or pests are exterminated in or around a location. Of course, a combination of these effects can occur. Generally, pest populations, activity, or both are desirably reduced by more than fifty percent, preferably more than 90 percent, and most preferably more than 99 percent. In general, a pesticidally effective amount, for agricultural purposes, is from about 0.0001 grams per hectare to about 5000 grams per hectare, preferably from about 0.0001 grams per hectare to about 500 grams per hectare, and is even more preferably from about 0.0001 gram per hectare to about 50 gram per hectare.

Descrição Detalhada desta InvençãoDetailed Description of this Invention

[00039] Este documento divulga moléculas da Fórmula Um

Figure img0007
em que:(A) R1 é selecionado do grupo consistindo em H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4)alquenila, (C3-C6)cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4)haloal- quila, (C3-C6)halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halocicloal- quenila, (C1-C4)haloalcóxi, S(C1-C4)alquila, S(O)(C1-C4)alquila, S(O)2 (C1-C4)alquila, S(C1-C4)haloalquila, S(O)(C1-C4)haloalquila, S(O)2(C1- C4)haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil-S(O)2NH2;(B) R2 é selecionado do grupo consistindo em H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4)alquenila, (C3-C6) cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4)halo- alquila, (C3-C6) halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halociclo- alquenila, (C1-C4) zhaloalcóxi, S(C1-C4)alquila, S(O) (C1-C4)alquila, S(O)2 (C1-C4)alquila, S(C1-C4)haloalquila, S(O) (C1-C4)haloalquila, S(O)2 (C1-C4)haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil- S(O)2NH2;(C) R3 é selecionado do grupo consistindo em H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4)alquenila, (C3-C6) cicloalquenila, (C2-C4alquinila, (C1-C4)alcóxi, (C1-C4)haloalquila, (C3-C6) halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halocicloalquenila, (C1-C4) haloalcóxi, S(C1-C4)alquila, S(O) (C1-C4)alquila, S(O)2 (C1-C4) alquila, S(C1-C4)haloalquila, S(O) (C1-C4)haloalquila, S(O)2 (C1-C4)halo- alquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil-S(O)2NH2;(D) R4 é selecionado do grupo consistindo em H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4)alquenila, (C3-C6) cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4)haloalquila, (C3-C6) halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halocicloalquenila, (C1-C4) haloalcóxi, S(C1-C4)alquila, S(O) (C1-C4)alquila, S(O)2 (C1-C4)alquila, S(C1-C4)haloalquila, S(O) (C1-C4)haloalquila, S(O)2 (C1-C4)haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil-S(O)2NH2; (E) R5 é selecionado do grupo consistindo em H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4)alquenila, (C3-C6) cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4)haloal- quila, (C3-C6) halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halocicloal- quenila, (C1-C4) haloalcóxi, S(C1-C4)alquila, S(O) (C1-C4)alquila, S(O)2 (C1-C4)alquila, S(C1-C4)haloalquila, S(O) (C1-C4)haloalquila, S(O)2 (C1-C4) haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil-S(O)2NH2;(F) R6 é selecionado do grupo consistindo em H e (C1-C4) alquil;(G) R7 é selecionado do grupo consistindo em H, F, Cl, Br e I;(H) R8 é selecionado do grupo consistindo em F, Cl, Br, I;(I) R9 é selecionado do grupo consistindo em H e (C1-C4) alquil;(J) R10 é selecionado do grupo consistindo em H, (C1-C4) alquila, (C2-C4)alquenila, (C1-C4)haloaquila, (C1-C4)alquil(C1-C4)alcóxi, C (=O)(C1-C4)alquila, e (C1-C4)alcóxiC(=O)(C1-C4)alquil;(K) R11 é selecionado do grupo consistindo em H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4)alque- nila, (C3-C6) cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4)halo- alquila, (C3-C6) halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halociclo- alquenila, (C1-C4) haloalcóxi, S(C1-C4)alquila, S(O) (C1-C4)alquila, S(O)2 (C1-C4) alquila, S(C1-C4)haloalquila, S(O) (C1-C4)haloalquila, S(O)2 (C1C4) haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil-S(O)2NH2;(L) R12 é selecionado do grupo consistindo em H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4) alqueni- la, (C3-C6) cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4)haloal- quila, (C3-C6) halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halocicloal- quenila, (C1-C4) haloalcóxi, S(C1-C4)alquila, S(O) (C1-C4)alquila, S(O)2 (C1-C4)alquila, S(C1-C4)haloalquila, S(O) (C1-C4)haloalquila, S(O)2 (C1-C4) haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil-S(O)2NH2; (M) R13 é selecionado do grupo consistindo em H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4)alque- nila, (C3-C6) cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4)halo- alquila, (C3-C6) halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halociclo- alquenila, (C1-C4) haloalcóxi, S(C1-C4)alquila, S(O) (C1-C4)alquila, S(O)2 (C1-C4)alquila, S(C1-C4)haloalquila, S(O) (C1-C4)haloalquila, S(O)2 (C1-C4)haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil- S(O)2NH2;(N) R14 é selecionado do grupo consistindo em H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4)al- quenila, (C3-C6) cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4) ha- loalquila, (C3-C6) halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halo- cicloalquenila, (C1-C4) haloalcóxi, S(C1-C4)alquila, S(O) (C1-C4)alquila, S(O)2 (C1-C4)alquila, S(C1-C4)haloalquila, S(O) (C1-C4)haloalquila, S(O)2 (C1-C4)haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil-S(O)2NH2;(O) R15 é selecionado do grupo consistindo em H, (C1-C4) alquila, (C2-C4)alquenila, (C1-C4)haloalquila, (C1-C4)alquil(C1-C4)alcóxi, C(=O)(C1-C4)alquil e (C1-C4)alcóxiC(=O)(C1-C4)alquil;(P) R16 é selecionado a partir do grupo consistindo em (C3-C8) cicloalquila, azetidinila, 2,5-dioxoimidazolidinila, 2,4-dioxo- 1,3-diazaspiro[4.4]nonanilisoxazolidinonila, imidazolidinonila, isoxa- zolidinonila, morfolinila, oxazolidinonila, oxetanila, piperazinila, pipe- ridinila, piranila, pirrolidinila, pirrolidinonila, tetra-hidrofuranila, tetra- hidropiranila, tetra-hidrotiofenila, tetra-hidrotiofenil-óxido, tetra- hidrotiofenil-dióxido, tietanila, tietanil-óxido, tietanil-dióxido e tioxoti- azolidinonila, em que cada cicloalquila, azetidinila, 2,5- dioxoimidazolidinila, 2,4-dioxo-1,3-diazaspiro [4.4]nonanilisoxazoli- dinonila, imidazolidinonila, isoxazolidinonila, morfolinila, oxazolidino- nila, oxetanila, piperazinila, piperidinila, piranila, pirrolidinila, pirroli- dinonila, tetra-hidrofuranila, tetra-hidropiranila, tetra-hidrotiofenila, tetra-hidrotiofenil-óxido, tetra-hidrotiofenil-dióxido, tietanila, tietanil- óxido, tietanil-dióxido e tioxotiazolidinonil podem ser opcionalmente substituídos por um ou mais substituintes selecionados dentre H, F, Cl, Br, I, CN, NH2, NO2, oxo, (C1-C4)alquila, (C1-C4)haloalquila, C(=O)O(C1-C4)alquila, (C=O)NH(C1-C4)alquila, (C=O)NH(C1-C4)haloalquila, C(=O)(C3-C6)ciclopropila, C(=O)(C1-C4) haloalquila, C(=O)(C1-C4) alquil(C1-C4)alcóxi e (C1-C4)alquil-morfolinil;(Q) Q1 e Q2 são independentemente selecionados a partir do grupo que consiste em O e S; eN-óxidos, sais de adição de ácido, derivados de sais, solva- tos, derivados de ésteres, polimorfos cristalinos, isótopos, estereoisô- meros resolvidos e tautômeros agricolamente aceitáveis das moléculas da Fórmula Um.[00039] This document discloses Formula One molecules
Figure img0007
wherein: (A) R1 is selected from the group consisting of H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C2-C4)alkenyl, (C3-C6)cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C3-C6)halocycloalkyl, (C2-C4)haloalkenyl, (C3-C6)halocycloal - chenyl, (C1-C4)haloalkoxy, S(C1-C4)alkyl, S(O)(C1-C4)alkyl, S(O)2(C1-C4)alkyl, S(C1-C4)haloalkyl, S (O)(C1-C4)haloalkyl, S(O)2(C1-C4)haloalkyl, (C1-C4)alkyl-S(O)2NH2 and (C1-C4)haloalkyl-S(O)2NH2;(B ) R2 is selected from the group consisting of H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C2-C4)alkenyl, (C3-C6) cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C3-C6) halocycloalkyl, (C2-C4)haloalkenyl, (C3-C6)halocycloalkenyl, (C1 -C4) zhaloalkoxy, S(C1-C4)alkyl, S(O)(C1-C4)alkyl, S(O)2 (C1-C4)alkyl, S(C1-C4)haloalkyl, S(O) (C1 -C4)haloalkyl, S(O)2 (C1-C4)haloalkyl, (C1-C4)alkyl-S(O)2NH2 and (C1-C4)haloalkyl-S(O)2NH2; (C) R3 is select ionated from the group consisting of H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C2-C4)alkenyl, (C3-C6)cycloalkenyl, ( C2-C4alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C3-C6) halocycloalkyl, (C2-C4)haloalkenyl, (C3-C6)halocycloalkenyl, (C1-C4) haloalkoxy, S(C1- C4)alkyl, S(O)(C1-C4)alkyl, S(O)2 (C1-C4)alkyl, S(C1-C4)haloalkyl, S(O)(C1-C4)haloalkyl, S(O) 2 (C1-C4)haloalkyl, (C1-C4)alkyl-S(O)2NH2 and (C1-C4)haloalkyl-S(O)2NH2; (D) R4 is selected from the group consisting of H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C2-C4)alkenyl, (C3-C6) cycloalkenyl, (C2-C4)alkynyl, (C1- C4)alkoxy, (C1-C4)haloalkyl, (C3-C6) halocycloalkyl, (C2-C4)haloalkenyl, (C3-C6)halocycloalkenyl, (C1-C4) haloalkoxy, S(C1-C4)alkyl, S(O ) (C1-C4)alkyl, S(O)2 (C1-C4)alkyl, S(C1-C4)haloalkyl, S(O)(C1-C4)haloalkyl, S(O)2 (C1-C4)haloalkyl , (C1-C4)alkyl-S(O)2NH2 and (C1-C4)haloalkyl-S(O)2NH2; (E) R5 is selected from the group consisting of H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C2-C4)alkenyl, (C3- C6) cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C3-C6) halocycloalkyl, (C2-C4)haloalkenyl, (C3-C6)halocycloalkenyl, (C1-C4) haloalkoxy, S(C1-C4)alkyl, S(O) (C1-C4)alkyl, S(O)2 (C1-C4)alkyl, S(C1-C4)haloalkyl, S(O) (C1-C4)haloalkyl, S(O)2 (C1-C4) haloalkyl, (C1-C4)alkyl-S(O)2NH2 and (C1-C4)haloalkyl-S(O)2NH2; (F) R6 is selected from the group consisting of H and (C1-C4) alkyl; (G) R7 is selected from the group consisting of H, F, Cl, Br and I; (H) R8 is selected from the group consisting of F, Cl, Br, I;(I) R9 is selected from the group consisting of H and (C1-C4) alkyl; (J) R10 is selected from the group consisting of H, (C1-C4) alkyl, (C2-C4)alkenyl, (C1-C1- C4)haloalkyl, (C1-C4)alkyl(C1-C4)alkoxy, C(=O)(C1-C4)alkyl, and (C1-C4)alkoxyC(=O)(C1-C4)alkyl;(K) R11 is selected from the group consisting of H, F, Cl, Br, I, CN, NH2, N O2, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C2-C4)alkenyl, (C3-C6) cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4 )haloalkyl, (C3-C6) halocycloalkyl, (C2-C4)haloalkenyl, (C3-C6)halocycloalkenyl, (C1-C4) haloalkoxy, S(C1-C4)alkyl, S(O)(C1- C4)alkyl, S(O)2(C1-C4)alkyl, S(C1-C4)haloalkyl, S(O)(C1-C4)haloalkyl, S(O)2 (C1C4) haloalkyl, (C1-C4) alkyl-S(O)2NH2 and (C1-C4)haloalkyl-S(O)2NH2;(L)R12 is selected from the group consisting of H, F, Cl, Br, I, CN, NH2, NO2, (C1- C4)alkyl, (C3-C6)cycloalkyl, (C2-C4)alkenyl, (C3-C6)cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C3-C6) halocycloalkyl, (C2-C4)haloalkenyl, (C3-C6)halocycloalkenyl, (C1-C4) haloalkoxy, S(C1-C4)alkyl, S(O) (C1-C4)alkyl, S (O)2 (C1-C4)alkyl, S(C1-C4)haloalkyl, S(O)(C1-C4)haloalkyl, S(O)2 (C1-C4) haloalkyl, (C1-C4)alkyl-S (O)2NH2 and (C1-C4)haloalkyl-S(O)2NH2; (M) R13 is selected from the group consisting of H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C2-C4)alkenyl, ( C3-C6) cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C3-C6) halocycloalkyl, (C2-C4)haloalkenyl, (C3-C6)halocyclo- alkenyl, (C1-C4) haloalkoxy, S(C1-C4)alkyl, S(O)(C1-C4)alkyl, S(O)2(C1-C4)alkyl, S(C1-C4)haloalkyl, S( O) (C1-C4)haloalkyl, S(O)2 (C1-C4)haloalkyl, (C1-C4)alkyl-S(O)2NH2 and (C1-C4)haloalkyl-S(O)2NH2;(N) R14 is selected from the group consisting of H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C2-C4)alkenyl, (C3-C6 ) cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C3-C6) halocycloalkyl, (C2-C4)haloalkenyl, (C3-C6)halocycloalkenyl, ( C1-C4) haloalkoxy, S(C1-C4)alkyl, S(O) (C1-C4)alkyl, S(O)2 (C1-C4)alkyl, S(C1-C4)haloalkyl, S(O) ( C1-C4)haloalkyl, S(O)2 (C1-C4)haloalkyl, (C1-C4)alkyl-S(O)2NH2 and (C1-C4)haloalkyl-S(O)2NH2;(O)R15 is selected from the group consisting of H, (C1-C4) alkyl, (C2-C4)alkenyl, (C1-C4)haloalkyl, (C1-C4)alkyl(C1-C4)alkoxy, C(=O)(C1-C4 )alkyl and (C1-C4)alkoxyC(=O)(C1-C4)alkyl; (P) R16 is selected from the group consisting of (C3-C8) cycloalkyl, azetidinyl, 2,5-dioxoimidazolidinyl, 2,4 -dioxo-1,3-diazaspiro[4.4]nonanilisoxazolidinonyl, imidazolidinonyl, isoxazolidinonyl, morpholinyl, oxazolidinonyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyranyl -hydrothiophenyl-oxide, tetrahydrothiophenyl-dioxide, thiethanyl, thiethanyl-oxide, thiethanyl-dioxide, and thioxothiazolidinonyl, wherein each cycloalkyl, azetidinyl, 2,5-dioxoimidazolidinyl, 2,4-dioxo-1,3-diazaspiro [ 4.4]nonanilisoxazolidinonyl, imidazolidinonyl, isoxazolidinonyl, morpholinyl, oxazolidinonyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydro opyranyl, tetrahydrothiophenyl, tetrahydrothiophenyl-oxide, tetrahydrothiophenyl-dioxide, thiethanyl, thiethanyl-oxide, thiethanyl-dioxide and thioxothiazolidinonyl may be optionally substituted by one or more substituents selected from H, F, Cl, Br, I, CN, NH2, NO2, oxo, (C1-C4)alkyl, (C1-C4)haloalkyl, C(=O)O(C1-C4)alkyl, (C=O)NH(C1-C4)alkyl, (C =O)NH(C1-C4)haloalkyl, C(=O)(C3-C6)cyclopropyl, C(=O)(C1-C4) haloalkyl, C(=O)(C1-C4)alkyl(C1-C4) )alkoxy and (C1-C4)alkyl-morpholinyl; (Q) Q1 and Q2 are independently selected from the group consisting of O and S; eN-oxides, acid addition salts, salt derivatives, solvates, ester derivatives, crystalline polymorphs, isotopes, resolved stereoisomers and agriculturally acceptable tautomers of the Formula One molecules.

[00040] As moléculas de Fórmula Um podem existir em diferentes formas isoméricas geométricas ou ópticas ou diferentes formas tauto- méricas. Um ou mais centros de quiralidade podem estar presentes, caso em que as moléculas de Fórmula Um podem estar presentes como enantiômeros puros, misturas de enantiômeros, diastereômeros puros ou misturas de diastereômeros. Apreciar-se-á por aqueles versados na técnica que um estereoisômero pode ser mais ativo do que os outros estereoisômeros. Estereoisômeros individuais podem ser obtidos por procedimentos sintéticos seletivos conhecidos, por procedimentos sintéticos convencionais usando materiais de partida resolvidos, ou por procedimentos de resolução convencionais. Pode haver ligações duplas presentes na molécula, caso em que os compostos de Fórmula Um podem existir como isômeros geométricos simples (cis ou trans, E ou Z) ou misturas de isômeros geométricos (cis e trans, E e Z). Centros de tautomerização podem estar presentes. Esta descrição cobre todos esses isômeros, tautômeros e misturas dos mesmos em todas as proporções.[00040] The molecules of Formula One can exist in different geometric or optical isomeric forms or different tautomeric forms. One or more centers of chirality may be present, in which case the Formula One molecules may be present as pure enantiomers, mixtures of enantiomers, pure diastereomers or mixtures of diastereomers. It will be appreciated by those skilled in the art that one stereoisomer may be more active than the other stereoisomers. Individual stereoisomers can be obtained by known selective synthetic procedures, by conventional synthetic procedures using resolved starting materials, or by conventional resolution procedures. There may be double bonds present in the molecule, in which case the compounds of Formula One may exist as single geometric isomers (cis or trans, E or Z) or mixtures of geometric isomers (cis and trans, E and Z). Tautomerization centers may be present. This description covers all these isomers, tautomers and mixtures thereof in all proportions.

[00041] Em outra modalidade, moléculas de Fórmula Um, o carboxamido e o fenila, que são ligados ao ciclopropano, estão na configuração R,R. Essa modalidade pode ser usada em combinação com asoutras modalidades de R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12,R13, R14, R15, R16, Q1 e Q2.[00041] In another embodiment, molecules of Formula One, the carboxamido and phenyl, which are linked to cyclopropane, are in the R,R configuration. This modality can be used in combination with the other modalities of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12,R13, R14, R15, R16, Q1 and Q2.

[00042] Em outra modalidade, R1 é selecionado do grupo consistindo em H, F e Cl. Essa modalidade pode ser usada em combinaçãocom as outras modalidades de R2, R3, R4, R5, R6, R7, R8, R9, R10, R11,R12, R13, R14, R15, R16, Q1 e Q2.[00042] In another modality, R1 is selected from the group consisting of H, F and Cl. This modality can be used in combination with the other modalities of R2, R3, R4, R5, R6, R7, R8, R9, R10, R11,R12, R13, R14, R15, R16, Q1 and Q2.

[00043] Em outra modalidade, R2 é selecionado do grupo consistindo em H, F, Cl, Br (C1-C4) alquil e (C1-C4)haloalquil. Essa modalidadepode ser usada em combinação com as outras modalidades de R1, R3,R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, Q1 e Q2.[00043] In another embodiment, R2 is selected from the group consisting of H, F, Cl, Br (C1-C4) alkyl and (C1-C4)haloalkyl. This modality can be used in combination with the other modalities of R1, R3,R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, Q1 and Q2.

[00044] Em outra modalidade, R2 é selecionado do grupo consistindo em H, F, Cl, Br, CH3, e CF3. Essa modalidade pode ser usada emcombinação com as outras modalidades de R1, R3, R4, R5, R6, R7, R8,R9, R10, R11, R12, R13, R14, R15, R16, Q1 e Q2.[00044] In another embodiment, R2 is selected from the group consisting of H, F, Cl, Br, CH3, and CF3. This modality can be used in combination with the other modalities of R1, R3, R4, R5, R6, R7, R8,R9, R10, R11, R12, R13, R14, R15, R16, Q1 and Q2.

[00045] Em outra modalidade, R3 é selecionado do grupo consistindo em H, F, Cl, (C1-C4)alquila, (C1-C4)haloalquil e (C1-C4)haloalcóxi.Essa modalidade pode ser usada em combinação com as outras modalidades de R1, R2, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15,R16, Q1 e Q2.[00045] In another embodiment, R3 is selected from the group consisting of H, F, Cl, (C1-C4)alkyl, (C1-C4)haloalkyl and (C1-C4)haloalkoxy. other modalities of R1, R2, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15,R16, Q1 and Q2.

[00046] Em outra modalidade, R3 é selecionado do grupo consistindo em H, F, Cl, CH3, CF3 e OCF3. Essa modalidade pode ser usadaem combinação com as outras modalidades de R1, R2, R4, R5, R6, R7,R8, R9, R10, R11, R12, R13, R14, R15, R16, Q1 e Q2.[00046] In another embodiment, R3 is selected from the group consisting of H, F, Cl, CH3, CF3 and OCF3. This modality can be used in combination with the other modalities of R1, R2, R4, R5, R6, R7,R8, R9, R10, R11, R12, R13, R14, R15, R16, Q1 and Q2.

[00047] Em outra modalidade, R4 é selecionado do grupo consistindo em H, F, Cl, Br, (C1-C4)alquil e (C1-C4)haloalquil. Essa modalidadepode ser usada em combinação com as outras modalidades de R1, R2,R3, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, Q1 e Q2.[00047] In another embodiment, R4 is selected from the group consisting of H, F, Cl, Br, (C1-C4)alkyl and (C1-C4)haloalkyl. This modality can be used in combination with the other modalities of R1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, Q1 and Q2.

[00048] Em outra modalidade, R4 é selecionado do grupo consistindo em H, F, Cl, Br, CH3, e CF3. Essa modalidade pode ser usada emcombinação com as outras modalidades de R1, R2, R3, R5, R6, R7, R8,R9, R10, R11, R12, R13, R14, R15, R16, Q1 e Q2.[00048] In another embodiment, R4 is selected from the group consisting of H, F, Cl, Br, CH3, and CF3. This modality can be used in combination with the other modalities of R1, R2, R3, R5, R6, R7, R8,R9, R10, R11, R12, R13, R14, R15, R16, Q1 and Q2.

[00049] Em outra modalidade, R5 é selecionado do grupo consistindo em H, F e Cl. Essa modalidade pode ser usada em combinaçãocom as outras modalidades de R1, R2, R3, R4, R6, R7, R8, R9, R10, R11,R12, R13, R14, R15, R16, Q1 e Q2.[00049] In another modality, R5 is selected from the group consisting of H, F and Cl. This modality can be used in combination with the other modalities of R1, R2, R3, R4, R6, R7, R8, R9, R10, R11,R12, R13, R14, R15, R16, Q1 and Q2.

[00050] Em outra modalidade, R6 é H. Essa modalidade pode serusada em combinação com as outras modalidades de R1, R2, R3, R4,R5, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, Q1 e Q2.[00050] In another modality, R6 is H. This modality can be used in combination with the other modalities of R1, R2, R3, R4, R5, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, Q1 and Q2.

[00051] Em outra modalidade, R7 é Cl. Essa modalidade pode serusada em combinação com as outras modalidades de R1, R2, R3, R4,R5, R6, R8, R9, R10, R11, R12, R13, R14, R15, R16, Q1 e Q2.[00051] In another embodiment, R7 is Cl. This modality can be used in combination with the other modalities of R1, R2, R3, R4,R5, R6, R8, R9, R10, R11, R12, R13, R14, R15, R16, Q1 and Q2.

[00052] Em outra modalidade, R8 é Cl. Essa modalidade pode serusada em combinação com as outras modalidades de R1, R2, R3, R4,R5, R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, Q1 e Q2.[00052] In another embodiment, R8 is Cl. This modality can be used in combination with the other modalities of R1, R2, R3, R4,R5, R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, Q1 and Q2.

[00053] Em outra modalidade, R9 é H. Essa modalidade pode serusada em combinação com as outras modalidades de R1, R2, R3, R4,R5, R6, R7, R8, R10, R11, R12, R13, R14, R15, R16, Q1 e Q2.[00053] In another modality, R9 is H. This modality can be used in combination with the other modalities of R1, R2, R3, R4, R5, R6, R7, R8, R10, R11, R12, R13, R14, R15, R16, Q1 and Q2.

[00054] Em outra modalidade, R10 é H. Essa modalidade pode serusada em combinação com as outras modalidades de R1, R2, R3, R4,R5, R6, R7, R8, R9, R11, R12, R13, R14, R15, R16, Q1 e Q2.[00054] In another modality, R10 is H. This modality can be used in combination with the other modalities of R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, R12, R13, R14, R15, R16, Q1 and Q2.

[00055] Em outra modalidade, R11 é H. Essa modalidade pode serusada em combinação com as outras modalidades de R1, R2, R3, R4,R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, Q1 e Q2.[00055] In another modality, R11 is H. This modality can be used in combination with the other modalities of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, Q1 and Q2.

[00056] Em outra modalidade, R12 é H. Essa modalidade pode serusada em combinação com as outras modalidades de R1, R2, R3, R4,R5, R6, R7, R8, R9, R10, R11, R13, R14, R15, R16, Q1 e Q2.[00056] In another modality, R12 is H. This modality can be used in combination with the other modalities of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R13, R14, R15, R16, Q1 and Q2.

[00057] Em outra modalidade, R13 é selecionado do grupo consistindo em H, Cl e haloalquil (C1-C4). Essa modalidade pode ser usadaem combinação com as outras modalidades de R1, R2, R3, R4, R5, R6,R7, R8, R9, R10, R11, R12, R14, R15, R16, Q1 e Q2.[00057] In another embodiment, R13 is selected from the group consisting of H, Cl and haloalkyl (C1-C4). This modality can be used in combination with the other modalities of R1, R2, R3, R4, R5, R6,R7, R8, R9, R10, R11, R12, R14, R15, R16, Q1 and Q2.

[00058] Em outra modalidade, R13 é selecionado do grupo consistindo em H, F, Cl e CF3. Essa modalidade pode ser usada em combinação com as outras modalidades de R1, R2, R3, R4, R5, R6, R7, R8, R9,R10, R11, R12, R14, R15, R16, Q1 e Q2.[00058] In another embodiment, R13 is selected from the group consisting of H, F, Cl and CF3. This modality can be used in combination with the other modalities of R1, R2, R3, R4, R5, R6, R7, R8, R9,R10, R11, R12, R14, R15, R16, Q1 and Q2.

[00059] Em outra modalidade, R14 é H. Essa modalidade pode serusada em combinação com as outras modalidades de R1, R2, R3, R4,R5, R6, R7, R8, R9, R10, R11, R12, R13, R15, R16, Q1 e Q2.[00059] In another modality, R14 is H. This modality can be used in combination with the other modalities of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R15, R16, Q1 and Q2.

[00060] Em outra modalidade, R15 é selecionado do grupo consistindo em H e alquil (C1-C4). Essa modalidade pode ser usada em combinação com as outras modalidades de R1, R2, R3, R4, R5, R6, R7, R8,R9, R10, R11, R12, R13, R14, R16, Q1 e Q2.[00060] In another embodiment, R15 is selected from the group consisting of H and (C1-C4) alkyl. This modality can be used in combination with the other modalities of R1, R2, R3, R4, R5, R6, R7, R8,R9, R10, R11, R12, R13, R14, R16, Q1 and Q2.

[00061] Em outra modalidade, R15 é selecionado do grupo consistindo em H e CH3. Essa modalidade pode ser usada em combinaçãocom as outras modalidades de R1, R2, R3, R4, R5, R6, R7, R8, R9, R10,R11, R12, R13, R14, R16, Q1 e Q2.[00061] In another modality, R15 is selected from the group consisting of H and CH3. This modality can be used in combination with the other modalities of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10,R11, R12, R13, R14, R16, Q1 and Q2.

[00062] Em outra modalidade, R16 é selecionado a partir do grupoque consiste em ciclopropila, ciclobutila, ciclopentila, ciclo-hexila, azetidinila, morfolinila, oxetanila, piranila, tetra-hidrotiofenila, tietanila, tietanil-óxido e tietanil-dióxido,[00062] In another embodiment, R16 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, morpholinyl, oxetanyl, pyranyl, tetrahydrothiophenyl, tiethanyl, tietanyl-oxide and tietanyl-dioxide,

[00063] em que cada ciclopropila, ciclobutila, ciclopentila, ciclohexila, azetidinila, morfolinila, oxetanila, piranila, tetra-hidrotiofenila,tietanila, tietanil-óxido e tietanil-dióxido podem ser opcionalmentesubstituídos por um ou mais substituintes selecionados do grupo consistindo em H, F, CN, C(=O)OC(CH3)3 e C(=O)CF3. Essa modalidadepode ser usada em combinação com as outras modalidades de R1, R2,R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Q1 e Q2.[00063] wherein each cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, morpholinyl, oxetanyl, pyranyl, tetrahydrothiophenyl, thietanyl, thietanyl-oxide and thietanyl-dioxide may be optionally substituted by one or more substituents selected from the group consisting of H, F, CN, C(=O)OC(CH3)3 and C(=O)CF3. This modality can be used in combination with the other modalities of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Q1 and Q2.

[00064] Em outra modalidade, Q1 é O. Essa modalidade pode serusada em combinação com as outras modalidades de R1, R2, R3, R4,R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 e Q2.[00064] In another modality, Q1 is O. This modality can be used in combination with the other modalities of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 and Q2.

[00065] Em outra modalidade, Q2 é O. Essa modalidade pode serusada em combinação com as outras modalidades de R1, R2, R3, R4,R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 e Q1.[00065] In another mode, Q2 is O. This mode can be used in combination with the other modalities of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 and Q1.

[00066] Em outra modalidade:(A) R1 é selecionado do grupo consistindo em H, F e Cl;(B) R2 é selecionado do grupo consistindo em H, F, Cl, Br, (C1-C4) alquil e (C1-C4)haloalquil;(C) R3 é selecionado do grupo consistindo em H, F, Cl, (C1-C4) alquila, (C1-C4)haloalquila, e (C1-C4)haloalcóxi;(D) R4 é selecionado do grupo consistindo em H, F, Cl, Br, (C1-C4) alquil e (C1-C4)haloalquil;(E) R5 é H;(F) R6 é H;(G) R7 é selecionado do grupo consistindo em Cl e Br;(H) R8 é selecionado do grupo consistindo em Cl e Br;(I) R9 é H;(J) R10 é H;(K) R11 é H;(L) R12 é H;(M) R13 é selecionado do grupo consistindo em H, Cl e (C1-C4) haloalquil;(N) R14 é H;(O) R15 é selecionado do grupo consistindo em H e (C1-C4) alquil;(P) R16 é selecionado do grupo consistindo em (C3-C8)ci- cloalquila, azetidinila, morfolinila, oxetanila, piranila, tetra-hidrotiofenila, tietanila, tietanil-óxido e tietanil-dióxido, em que cada cicloalquila, aze- tidinila, morfolinila, oxetanila, piranila, tetra-hidrofenila, tietanila, tietanil- óxido e tietanil-dióxido podem ser opcionalmente substituídos por um ou mais substituintes selecionados do grupo consistindo em H, F, CN, C(=O)O(C1-C4)alquila, C(=O)(C3-C6)ciclopropila, C(=O)(C1-C4)haloal- quil e C(=O)(C1-C4)alquil(C1-C4)alcóxi; e(Q) Q1 e Q2 são O.[00066] In another embodiment: (A) R1 is selected from the group consisting of H, F and Cl; (B) R2 is selected from the group consisting of H, F, Cl, Br, (C1-C4) alkyl and (C1 -C4)haloalkyl; (C)R3 is selected from the group consisting of H, F, Cl, (C1-C4)alkyl, (C1-C4)haloalkyl, and (C1-C4)haloalkoxy; (D)R4 is selected from group consisting of H, F, Cl, Br, (C1-C4) alkyl and (C1-C4)haloalkyl; (E) R5 is H; (F) R6 is H; (G) R7 is selected from the group consisting of Cl and Br;(H) R8 is selected from the group consisting of Cl and Br;(I) R9 is H;(J) R10 is H;(K) R11 is H;(L) R12 is H;(M) R13 is selected from the group consisting of H, Cl and (C1-C4) haloalkyl; (N) R14 is H; (O) R15 is selected from the group consisting of H and (C1-C4) alkyl; (P) R16 is selected from the group consisting of (C3-C8)cycloalkyl, azetidinyl, morpholinyl, oxetanyl, pyranyl, tetrahydrothiophenyl, thietanyl, thietanyl-oxide and thietanyl-dioxide, where each cycloalkyl, azetidinyl, morpholinyl, oxetanyl, pyranyl, tetra- hydrophenyl, tiethanyl, tie tanyl-oxide and thiethanyl-dioxide may be optionally substituted by one or more substituents selected from the group consisting of H, F, CN, C(=O)O(C1-C4)alkyl, C(=O)(C3-C6) cyclopropyl, C(=O)(C1-C4)haloalkyl and C(=O)(C1-C4)alkyl(C1-C4)alkoxy; and(Q) Q1 and Q2 are O.

[00067] Em outra modalidade:(A) R1 é selecionado do grupo consistindo em H e Cl;(B) R2 é selecionado do grupo consistindo em H, Cl, Br, CH3 e CF3;(C) R3 é selecionado do grupo consistindo em H, Cl, CH3 e CF3, OCF3;(D) R4 é selecionado do grupo consistindo em H, F, Cl, Br, CH3 e CF3;(E) R5 é H;(F) R6 é H;(G) R7 é selecionado do grupo consistindo em Cl e Br;(H) R8 é selecionado do grupo consistindo em Cl e Br;(I) R9 é H;(J) R10 é H;(K) R11 é H;(L) R12 é H;(M) R13 é selecionado do grupo consistindo em H, Cl e CF3;(N) R14 é H;(O) R15 é selecionado do grupo consistindo em H e CH3;(P) R16 é selecionado do grupo consistindo em (C3-C8)ci- cloalquila, azetidinila, morfolinila, oxetanila, piranila, tetra-hidrotiofenila, tietanila, tietanil-óxido e tietanil-dióxido, em que cada cicloalquila, aze- tidinila, morfolinila, oxetanila, piranila, tetra-hidrofenila, tietanila, tietanil- óxido e tietanil-dióxido podem ser opcionalmente substituídos por um ou mais substituintes selecionados do grupo consistindo em H, F, CN, C(=O)O(C1-C4)alquila, C(=O)(C3-C6)ciclopropila, C(=O)(C1-C4)haloal- quil e C(=O)(C1-C4)alquil(C1-C4)alcóxi; e(Q) Q1 e Q2 são O.Preparação de ácidos ciclopropil carboxílicos 123456 9[00067] In another embodiment: (A) R1 is selected from the group consisting of H and Cl; (B) R2 is selected from the group consisting of H, Cl, Br, CH3 and CF3; (C) R3 is selected from the group consisting of in H, Cl, CH3 and CF3, OCF3;(D) R4 is selected from the group consisting of H, F, Cl, Br, CH3 and CF3;(E) R5 is H;(F) R6 is H;(G) R7 is selected from the group consisting of Cl and Br;(H) R8 is selected from the group consisting of Cl and Br;(I) R9 is H;(J) R10 is H;(K) R11 is H;(L) R12 is H;(M) R13 is selected from the group consisting of H, Cl and CF3;(N) R14 is H;(O) R15 is selected from the group consisting of H and CH3;(P) R16 is selected from the group consisting of (C3-C8)cycloalkyl, azetidinyl, morpholinyl, oxetanyl, pyranyl, tetrahydrothiophenyl, thietanyl, thietanyl-oxide and thiethanyl-dioxide, where each cycloalkyl, azetidinyl, morpholinyl, oxetanyl, pyranyl, tetrahydrophenyl, thiethanyl, thiethanyl-oxide and thiethanyl-dioxide may be optionally substituted by one or more substituents selected from the group consisting of having in H, F, CN, C(=O)O(C1-C4)alkyl, C(=O)(C3-C6)cyclopropyl, C(=O)(C1-C4)haloalkyl and C(= O)(C1-C4)alkyl(C1-C4)alkoxy; and(Q) Q1 and Q2 are O. Preparation of cyclopropyl carboxylic acids 123456 9

[00068] Estilbenos 1-1, em que R , R , R , R , R , R , e R são conforme divulgado anteriormente, podem ser tratados com uma base, tal como hidróxido de sódio na presença de uma fonte de carbeno, tal como clorofórmio ou bromofórmio e um catalisador de transferência de fase, tal como cloreto de N-benzil-N,N-dietiletanamínio em um solvente polar prótico, tal como água em temperaturas de cerca de 0°C a cerca de 40°C para fornecer diaril ciclopropanos 1-2, em que R1, R2, R3, R4, R5, R6, R7, R8, e R9 são conforme divulgado anteriormente (Esquema 1, etapa a). O tratamento de diaril ciclopropanos 1-2 com um metal de transição, tal como cloreto de rutênio(III) na presença de um oxidante estequiométrico, tal como periodato de sódio em uma mistura de solvente, preferencialmente água, acetato de etila e acetonitrila em temperaturas de cerca de 0°C a cerca de 40°C pode fornecer ácidos ciclo- 1 2345678 9propil carboxílicos 1-3, em que R , R , R , R , R , R , R , R , e R são conforme divulgado anteriormente (Esquema 1, etapa b).Esquema 1

Figure img0008
[00068] Stilbenes 1-1, wherein R , R , R , R , R , R , and R are as disclosed above, can be treated with a base such as sodium hydroxide in the presence of a carbene source such as such as chloroform or bromoform and a phase transfer catalyst such as N-benzyl-N,N-diethylethanaminium chloride in a polar protic solvent such as water at temperatures from about 0°C to about 40°C to provide diaryl cyclopropanes 1-2, wherein R1, R2, R3, R4, R5, R6, R7, R8, and R9 are as disclosed above (Scheme 1, step a). Treatment of diaryl cyclopropanes 1-2 with a transition metal such as ruthenium(III) chloride in the presence of a stoichiometric oxidant such as sodium periodate in a solvent mixture, preferably water, ethyl acetate and acetonitrile at temperatures from about 0°C to about 40°C can provide 1-3 cyclo-1,234,678,9propyl carboxylic acids 1-3, wherein R, R, R, R, R, R, R, R, and R are as previously disclosed ( Scheme 1, step b). Scheme 1
Figure img0008

[00069] Em ainda outras modalidades, 1-3 podem ser preparados a partir de aril cetona 1.5-1, em que R1, R2, R3, R4 e R5 são como divulgado previamente, e R6 é metil. A acetofenona 1.5-1 pode reagir em uma primeira etapa com um carbânion de fosfonato estabilizado, gerado pelo tratamento de um fosfonato, tal como o 2-(dietoxifosforil)- acetato de etila, com uma base forte, como hidreto de sódio ou terc- butóxido de potássio, em um solvente aprótico polar, tal como tetra- hidrofurano, a uma temperatura de cerca de 0°C a cerca de 5°C (Esquema 1.5, etapa a). Essa reação, como muitas outras envolvendo o tratamento de aldeídos ou cetonas com carbânions de fosfonato estabilizados para produzir olefinas, será prontamente reconhecida por alguém versado na técnica como a olefinação de Horner-Wadsworth- Emmons. Em uma segunda etapa, o a,3-éster insaturado 1.5-2, em que R1, R2, R3, R4, R5 e R6 são como definido acima, pode ser tratado com um agente redutor, por exemplo, um hidreto metálico como hidre- to de di-isobutilalumínio, em um solvente hidrocarboneto aromático, como tolueno, a uma temperatura de cerca de-78°C a cerca de 22°C para produzir o álcool primário intermediário 1.5-3 (Esquema 1.5, etapa b), em que R1, R2, R3, R4, R5 e R6 são como definido acima e R9 é como divulgado previamente. A proteção do álcool primário 1.5-3 é necessária para a conclusão bem sucedida de transformações químicas subsequentes, e uma ampla variedade de estratégias de grupo de proteção poderia ser utilizada. Por exemplo, o tratamento do álcool 1.5-3 com 3,4-di-hidro-2-H-pirano na presença de uma quantidade catalítica de um ácido orgânico, tal como ácido para-toluenossulfônico mono-hidratado, em um solvente aprótico, como éter dietílico, de uma temperatura de cerca de 0°C até cerca da temperatura ambiente proporciona o álcool protegido 1.5-4 com tetra-hidro-2-H-pirano (THP) (Esquema 1.5, etapa c), em que R1, R2, R3, R4, R5, R6 e R9 são como definido acima. O intermediário estiril protegido com THP pode ser convertido no intermediário ciclopropano protegido com THP 1.5-5, em que R1, R2, R3, R4, R5, R6 e R9 são como definido acima e R7 e R8 são como divulgado previamente, através do tratamento com fonte de car- beno, tal como clorofórmio, na presença de uma base, tal como hidróxido de sódio ou de potássio, e de um catalisador, tal como hexafluoro- fosfato de tetrabutilamônio a uma temperatura de cerca de 25 a 45°C (Esquema 1.5, etapa d). A desproteção do intermediário ciclopropano protegido com THP 1.5-5, em que R1, R2, R3, R4, R5, R6, R7, R8 e R9 , ,,,,,,,são como definido acima, pode ser atingida através do tratamento com uma quantidade catalítica de um ácido orgânico, tal como ácido para- toluenossulfônico mono-hidratado, em solvente prótico polar, tal como metanol, a uma temperatura de cerca de 22°C para produzir o inter-mediário ciclopropil metanol 1.5-6 (Esquema 1.5, etapa e). A oxidação 1 23456do intermediário álcool primário 1.5-6, em que R , R , R , R , R , R , R7, R8 e R9 são como definido acima, pode ser atingida através do uso de uma ampla variedade de reagentes e condições conhecidos na técnica (Figadere, B. e Franck, X., "Carboxylic Acids: Synthesis from Alcohols" Science of Synthesis 2006, (20a) pp 173 - 204), muitos dos quais oferecem compatibilidade e seletividade diferencial por grupo funcional. Por exemplo, o tratamento do intermediário álcool 1.5-6 com soluções de trióxido de cromo em soluções diluídas de ácido sulfúrico e acetona, reagente de Jones, proporciona o ácido ciclopropil carboxí- 1 2345678 9lico 1-3, em que R , R , R , R , R , R , R , R e R são como definido acima (Esquema 1.5, etapa f).Esquema 1.5

Figure img0009
Figure img0010
[00069] In still other embodiments, 1-3 can be prepared from aryl ketone 1.5-1, wherein R1, R2, R3, R4 and R5 are as previously disclosed, and R6 is methyl. Acetophenone 1.5-1 can react in a first step with a stabilized phosphonate carbanion, generated by treating a phosphonate, such as 2-(diethoxyphosphoryl)-ethyl acetate, with a strong base, such as sodium hydride or tert. potassium butoxide, in a polar aprotic solvent, such as tetrahydrofuran, at a temperature from about 0°C to about 5°C (Scheme 1.5, step a). This reaction, like many others involving the treatment of aldehydes or ketones with stabilized phosphonate carbanions to produce olefins, will be readily recognized by one of skill in the art as Horner-Wadsworth-Emmons olefination. In a second step, the α,3-unsaturated ester 1.5-2, wherein R1, R2, R3, R4, R5 and R6 are as defined above, can be treated with a reducing agent, eg a metal hydride such as a metal hydride. diisobutylaluminum oxide, in an aromatic hydrocarbon solvent such as toluene, at a temperature of from about -78°C to about 22°C to produce the primary alcohol intermediate 1.5-3 (Scheme 1.5, step b), wherein R1, R2, R3, R4, R5 and R6 are as defined above and R9 is as previously disclosed. The protection of primary alcohol 1.5-3 is necessary for the successful completion of subsequent chemical transformations, and a wide variety of protecting group strategies could be used. For example, treating alcohol 1.5-3 with 3,4-dihydro-2-H-pyran in the presence of a catalytic amount of an organic acid, such as para-toluenesulfonic acid monohydrate, in an aprotic solvent, as diethyl ether, from a temperature of about 0°C to about room temperature provides the alcohol 1.5-4 protected with tetrahydro-2-H-pyran (THP) (Scheme 1.5, step c), where R 1 . R2, R3, R4, R5, R6 and R9 are as defined above. The styryl THP-protected intermediate can be converted to the THP-protected cyclopropane intermediate 1.5-5, wherein R1, R2, R3, R4, R5, R6 and R9 are as defined above and R7 and R8 are as previously disclosed, through the treatment with a carbene source, such as chloroform, in the presence of a base, such as sodium or potassium hydroxide, and a catalyst, such as tetrabutylammonium hexafluorophosphate at a temperature of about 25 to 45°C ( Scheme 1.5, step d). Deprotection of the THP 1.5-5 protected cyclopropane intermediate, wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9, ,,,,,,, are as defined above, can be achieved by treatment with a catalytic amount of an organic acid, such as para-toluenesulfonic acid monohydrate, in a polar protic solvent, such as methanol, at a temperature of about 22°C to produce the intermediate cyclopropyl methanol 1.5-6 (Scheme 1.5, step e). Oxidation 1,23456 of the primary alcohol intermediate 1.5-6, wherein R , R , R , R , R , R , R7, R8 and R9 are as defined above, can be achieved through the use of a wide variety of known reagents and conditions in the technique (Figadere, B. and Franck, X., "Carboxylic Acids: Synthesis from Alcohols" Science of Synthesis 2006, (20a) pp 173 - 204), many of which offer compatibility and differential selectivity by functional group. For example, treatment of the alcohol intermediate 1.5-6 with solutions of chromium trioxide in dilute solutions of sulfuric acid and acetone, Jones reagent, provides the cyclopropyl carboxylic acid 1-3, where R , R , R , R , R , R , R , R and R are as defined above (Scheme 1.5, step f).
Figure img0009
Figure img0010

Preparação de estilbenosPreparation of stilbenes

[00070] Estilbenos 1-1 podem ser preparados por diversos métodos diferentes, conforme descrito no Esquema 2. Fenil carbonilas 2-1, em que R1, R2, R3, R4, R5 e R6 são como divulgado previamente, podem ser tratadas com alcóxi benzil fosfonatos 2-2 na presença de uma base, tal como metóxido de sódio, em um solvente aprótico polar, tal como N,N-dimetilformamida, em temperaturas de cerca de -10°C até cerca de 30°C e subsequentemente aquecidas a 40°C até cerca de80°C para prover estilbenos 1-1 (Esquema 2, etapa a).Esquema 2

Figure img0011
Figure img0012
[00070] Stilbenes 1-1 can be prepared by several different methods as described in Scheme 2. Phenyl carbonyls 2-1, wherein R1, R2, R3, R4, R5 and R6 are as previously disclosed, can be treated with alkoxy benzyl phosphonates 2-2 in the presence of a base, such as sodium methoxide, in a polar aprotic solvent, such as N,N-dimethylformamide, at temperatures from about -10°C to about 30°C and subsequently heated to 40°C to about 80°C to provide 1-1 stilbenes (Scheme 2, step a).Scheme 2
Figure img0011
Figure img0012

[00071] Haletos de arila 2-3, em que R1, R2alquilaR4 e R5 são como divulgado previamente, podem ser tratados com vinilbenzenos 2-4, em que R6 e R9 são como divulgado previamente, na presença de um catalisador de metal de transição, tal como acetato de palá- alquiladio(II), e de um ligante bisfosfina, tal como 1,1'- bis(difenilfosfino)ferroceno, em um solvente básico, tal como trieti- lamina, a temperaturas de 60°C até cerca de 100°C para prover es- tilbenos 1-1 (Esquema 2, etapa b). Alternativamente, haletos de arila 2-3 podem ser tratados com vinilboronatos 2-5, em que R6 e R9 são como divulgado previamente, na presença de um catalisador de metal de transição, tal como tetraquis(trifenilfosfina) paládio(0), e uma base, tal como carbonato de potássio, em uma mistura de solventes, tal como 1,2-dimetoxietano e água, a temperaturas de cerca de 60°C até cerca de 100°C para prover estilbenos 1-1 (Esquema 2, etapa c).[00071] Aryl halides 2-3, wherein R1, R2alkylR4 and R5 are as previously disclosed, can be treated with vinylbenzenes 2-4, wherein R6 and R9 are as previously disclosed, in the presence of a transition metal catalyst , such as palladium(II)-alkylacetate, and a bisphosphine linker, such as 1,1'-bis(diphenylphosphino)ferrocene, in a basic solvent, such as triethylamine, at temperatures from 60°C to about 100°C to provide 1-1 stilbenes (Scheme 2, step b). Alternatively, aryl halides 2-3 can be treated with vinylboronates 2-5, where R6 and R9 are as previously disclosed, in the presence of a transition metal catalyst, such as tetrakis(triphenylphosphine) palladium(0), and a base, such as potassium carbonate, in a mixture of solvents, such as 1,2-dimethoxyethane and water, at temperatures from about 60°C to about 100°C to provide 1-1 stilbenes (Scheme 2, step c ).

[00072] Em ainda outra modalidade, estilbenos 1-1 também podem ser preparados pelo método de olefinação de Wittig (Chalal, M.; Vervandier-Fasseur, D.; Meunier, P.; Cattey, H.; Hierso, J.- C.Tetrahedron 2012, 68, 3899-3907) como descrito no Esquema 2.5. Fenil carbonilas 2-1, em que R1, R2, R3, R4 e R5 são como divulgado previamente e R6 é H, podem ser tratadas com cloretos de alcóxi benzil trifenilfosfônio 2.5-2 na presença de uma base, tal como n- butil lítio, em um solvente aprótico polar, tal como tetra-hidrofurano, a temperaturas de cerca de-78°C até a temperatura ambiente para prover estilbenos 1-1 (Esquema 2.5, etapa a). Esquema 2.5

Figure img0013
[00072] In yet another modality, stilbenes 1-1 can also be prepared by the Wittig olefination method (Chalal, M.; Vervandier-Fasseur, D.; Meunier, P.; Cattey, H.; Hierso, J.- C. Tetrahedron 2012, 68, 3899-3907) as described in Scheme 2.5. Phenyl carbonyls 2-1, where R1, R2, R3, R4 and R5 are as previously disclosed and R6 is H, can be treated with 2.5-2 benzyl benzyl phosphonium alkoxy chlorides in the presence of a base such as n-butyl lithium , in a polar aprotic solvent, such as tetrahydrofuran, at temperatures from about -78°C to room temperature to provide stilbenes 1-1 (Scheme 2.5, step a). Scheme 2.5
Figure img0013

Preparação de ciclopropil amidasPreparation of cyclopropyl amides

[00073] Ciclopropil amidas 3-3, em que R , R , R , R , R , R , R , R8 9 10 11 12 13 14 2 15 16, R , R , R , R , R , R , Q , R e R são como divulgado previamente, podem ser preparadas através do tratamento com aminas ou sais de amina 3-2, em que R10, R11, R12, R13, R14, Q2 e R15 e R16 são como divulgado previamente, e ácidos carboxílicos 3-1, em que A é um grupo de ativação e R1, R2, R3, R4, R5, R6, R7, R8 e R9 são como ,,,,,,,divulgado previamente, com uma base como trietilamina, di-isopro- piletilamina, 4-metilmorfolina ou 4-dimetilaminopiridina em um solvente aprótico anidro, tal como diclorometano, tetra-hidrofurano, 1,2-dicloroe- tano, dimetilformamida ou qualquer combinação dos mesmos, a tem-peraturas entre cerca de 0°C e cerca de 120°C (Esquema 3, etapa a).[00073] Cyclopropyl amides 3-3, wherein R , R , R , R , R , R , R , R8 9 10 11 12 13 14 2 15 16, R , R , R , R , R , R , Q , R and R are as previously disclosed, can be prepared by treatment with amines or amine salts 3-2, where R10, R11, R12, R13, R14, Q2 and R15 and R16 are as previously disclosed, and carboxylic acids 3 -1, where A is an activating group and R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as previously disclosed, with a base such as triethylamine, diisopro - piletylamine, 4-methylmorpholine or 4-dimethylaminopyridine in an anhydrous aprotic solvent, such as dichloromethane, tetrahydrofuran, 1,2-dichloroethane, dimethylformamide or any combination thereof, at temperatures between about 0°C and about 120°C (Scheme 3, step a).

[00074] Ácidos carboxílicos ativados 3-1 podem ser um haleto de ácido, tal como um cloreto de ácido, um brometo de ácido ou um fluo- reto de ácido; um éster carboxílico, tal como um para-nitrofenil éster, um pentafluorofenil éster, um éster de (hidróxi-imínio)cianoacetato de etila, um metil éster, um etil éster, um benzil éster, um N- hidroxissuccinimidil éster, um hidroxibenzotriazol-1-il ester ou um hi- droxipiridiltriazol-1-il éster; uma O-acilisoureia; um anidrido de ácido; ou um tioéster. Cloretos de ácidos podem ser preparados a partir dos ácidos carboxílicos correspondentes através de tratamento com um reagente de cloração desidratante, tal como cloreto de oxalila ou cloreto de tionila. Ésteres carboxílicos ativados 3-1 podem ser preparados a partir de ácidos carboxílicos in situ com um sal de urônio, tal como 3- óxido hexafluorofosfato de 1- [bis(dimetilamino)metileno]-1H-1,2,3-tria- zolo[4,5-b]piridínio (HATU), hexafluorofosfato de O-(benzotriazol-1-il)- N,N,N',N'-tetrametilurônio (HBTU) ou hexafluorofosfato de (1-ciano-2- etóxi-2-oxoetilidenaminóxi)dimetilamino-morfolino-carbênio (COMU). Ésteres carboxílicos ativados 3-1 também podem ser preparados a partir de ácidos carboxílicos in situ com um sal de fosfônio, tal como hexafluorofosfato de benzotriazol-1-il-oxitripirrolidinofosfônio (PyBop). Ésteres carboxílicos ativados 3-1 também podem ser preparados a partir de ácidos carboxílicos in situ com um reagente de acoplamento, tal como 1-(3-dimetilaminopropil)-3-etilcarbodi-imida, ou diciclo-hexil- carbodi-imida, na presença de um triazol, tal como hidroxibenzotria- zoLmonohidratado (HOBt) ou 1-hidróxi-7-azabenzotriazol (HOAt). O - Acilisoureias podem ser preparadas com uma carbodi-imida desidra- tante, tal como 1-(3-dimetilamino propil)-3-etilcarbodi-imida ou diciclo- hexilcarbodi-imida. Ésteres carboxílicos ativados 3-1 também podem ser preparados a partir de ácidos carboxílicos in situ com um reagente de acoplamento, tal como hexafluorofosfato de 2-cloro-1,3-dimetilimi- dazolidínio (CIP), na presença de um triazol, tal como hidroxibenzo- triazoLmonohidratado (HOBt) ou 1-hidróxi-7-azabenzotriazol (HOAt). Ésteres carboxílicos ativados 3-1 também podem ser preparados a partir de ácidos carboxílicos in situ com um reagente de acoplamento, tal como 2,4,6-trióxido de 2,4,6-tripropil-1,3,5,2,4,6-trioxatrifosfinano (T3P®) na presença de uma base, tal como piridina.[00074] Activated carboxylic acids 3-1 can be an acid halide, such as an acid chloride, an acid bromide or an acid fluoride; a carboxylic ester, such as a para-nitrophenyl ester, a pentafluorophenyl ester, an ethyl (hydroxyiminium)cyanoacetate ester, a methyl ester, an ethyl ester, a benzyl ester, an N-hydroxysuccinimidyl ester, a hydroxybenzotriazol-1 -yl ester or a hydroxypyridyltriazol-1-yl ester; an O-acyl isourea; an acid anhydride; or a thioester. Acid chlorides can be prepared from the corresponding carboxylic acids by treatment with a dehydrating chlorinating reagent such as oxalyl chloride or thionyl chloride. Activated carboxylic esters 3-1 can be prepared from carboxylic acids in situ with a uronium salt such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole 3-hexafluorophosphate oxide [4,5-b]pyridinium (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or (1-cyano-2-ethoxy-hexafluorophosphate) 2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium (COMU). Activated carboxylic esters 3-1 can also be prepared from carboxylic acids in situ with a phosphonium salt such as benzotriazol-1-yl-oxytripyrrolidinephosphonium hexafluorophosphate (PyBop). Activated carboxylic esters 3-1 can also be prepared from carboxylic acids in situ with a coupling reagent, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or dicyclohexylcarbodiimide, in the presence of a triazole, such as hydroxybenzotriazolmonohydrate (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt). O - Acylisoureas can be prepared with a dehydrating carbodiimide, such as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide or dicyclohexylcarbodiimide. Activated carboxylic esters 3-1 can also be prepared from carboxylic acids in situ with a coupling reagent such as 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP) in the presence of a triazole such as hydroxybenzotriazolmonohydrate (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt). Activated carboxylic esters 3-1 can also be prepared from carboxylic acids in situ with a coupling reagent such as 2,4,6-trioxide 2,4,6-tripropyl-1,3,5,2,4 ,6-Trioxatriphosphinan (T3P®) in the presence of a base such as pyridine.

[00075] Ciclopropil amidas 3-3, em que R16 é tietanil ou tetra-hidro- tiofenil e R15 é conforme divulgado anteriormente, podem ser oxidadas em sulfóxido ou sulfona correspondente pelo tratamento com cerca de um equivalente de ácido meta-cloroperoxibenzoico em um solvente apró- tico polar como diclorometano (sulfóxido) ou cerca de dois equivalentes de ácido meta-cloroperoxibenzoico (sulfona) em temperaturas entre cerca de 0°C a cerca de 40°C. Alternativamente, as ciclopropil amidas 3-3, em que R16 é tietanil ou tetra-hidrotiofenil e R15 é conforme divulgado an-teriormente, podem ser oxidadas em sulfóxido ou sulfona correspondente pelo tratamento com um equivalente de perborato de sódio em um sol-vente prótico como ácido acético (sulfóxido) ou dois equivalentes de per- borato de sódio (sulfona). A oxidação pode ser desempenhada em tem-peraturas entre cerca de 40°C a cerca de 100°C usando cerca de 1,5 equivalentes de perborato de sódio para fornecer misturas separáveis cromatograficamente de sulfóxido e sulfona ciclopropil amidas 3-3.[00075] Cyclopropyl amides 3-3, wherein R16 is thiethanyl or tetrahydrothiophenyl and R15 is as disclosed above, can be oxidized to the corresponding sulfoxide or sulfone by treatment with about one equivalent of meta-chloroperoxybenzoic acid in a solvent polar aprotic such as dichloromethane (sulfoxide) or about two equivalents of meta-chloroperoxybenzoic acid (sulfone) at temperatures between about 0°C to about 40°C. Alternatively, cyclopropyl amides 3-3, wherein R16 is thiethanyl or tetrahydrothiophenyl and R15 is as disclosed above, can be oxidized to the corresponding sulfoxide or sulfone by treatment with one equivalent of sodium perborate in a protic solvent. as acetic acid (sulfoxide) or two equivalents of sodium perborate (sulfone). The oxidation can be performed at temperatures between about 40°C to about 100°C using about 1.5 equivalents of sodium perborate to provide chromatographically separable mixtures of sulfoxide and sulfone cyclopropyl amides 3-3.

[00076] Ciclopropil amidas 3-3, em que R3 é NO2 podem ser reduzidas em NH2 correspondente pelo tratamento com uma fonte de ácido, como cloreto de amônio e ferro em um solvente prótico, como metanol, água, ou qualquer combinação destes, em temperaturas de cerca de 20°C a cerca de 60°C.Esquema 3

Figure img0014
[00076] Cyclopropyl amides 3-3, where R3 is NO2 can be reduced to the corresponding NH2 by treatment with an acid source such as ammonium chloride and iron in a protic solvent such as methanol, water, or any combination thereof, in temperatures from about 20°C to about 60°C.
Figure img0014

[00077] Ciclopropil amidas 4-3, em que R , R , R , R , R , R , R , R8 9 1 10 11 12 13 14 15 16, R , Q , R , R , R , R , R , R , e R são conforme divulgado anteriormente, podem ser preparadas pelo tratamento com aminas ou sais de amina 4-2, em que R15 e R16 são conforme divulgado an-teriormente, e ácidos carboxílicos ativados 4-1, em que A é um gru- 1 2 3 4 5 6 7 8 9 1 10 11 12po de ativação, e R , R , R , R , R , R , R , R , R , Q , R , R , R , R13, e R14 são conforme divulgado anteriormente, com uma base, tal como trietilamina, di-isopropiletilamina, 4-metilmorfolina, ou 4- dimetilaminopiridina em um solvente aprótico anidro, tal como diclo- rometano, tetra-hidrofurano, 1,2-dicloroetano, dimetilformamida, ou qualquer combinação dos mesmos, em temperaturas entre cerca de 0°C e cerca de 120°C (Esquema 4, etapa a).[00077] Cyclopropyl amides 4-3, wherein R , R , R , R , R , R , R , R8 9 1 10 11 12 13 14 15 16, R , Q , R , R , R , R , R , R 1 and R are as disclosed above, can be prepared by treatment with amines or amine salts 4-2, where R 15 and R 16 are as disclosed above, and activated carboxylic acids 4-1, where A is a group. - 1 2 3 4 5 6 7 8 9 1 10 11 12p of activation, and R , R , R , R , R , R , R , R , R , Q , R , R , R , R13, and R14 are as per disclosed above, with a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine, or 4-dimethylaminopyridine in an anhydrous aprotic solvent such as dichloromethane, tetrahydrofuran, 1,2-dichloroethane, dimethylformamide, or any combination thereof, at temperatures between about 0°C and about 120°C (Scheme 4, step a).

[00078] Ácidos carboxílicos ativados 4-1 podem ser um haleto de ácido, tal como um cloreto de ácido, um brometo de ácido ou um fluoreto de ácido; um éster carboxílico, tal como um para-nitrofenil éster, um pentafluorofenil éster, um éster de (hidróxi- imínio)cianoacetato de etila, um metil éster, um etil éster, um benzil éster, um N-hidroxissuccinimidil éster, um hidroxibenzotriazol-1-il ester ou um hidroxipiridiltriazol-1-il éster; uma O-acilisoureia; um anidrido de ácido; ou um tioéster. Cloretos de ácidos podem ser preparados a partir dos ácidos carboxílicos correspondentes através de tratamento com um reagente de cloração desidratante, tal como cloreto de oxalila ou cloreto de tionila. Ésteres carboxílicos ativados 4-1 podem ser preparados a partir de ácidos carboxílicos in situ com um sal de urônio, tal como 3-óxido hexafluorofosfato de 1- [bis(dimetilamino)metileno]-1H-1,2,3-triazolo[4,5-b]piridínio (HATU), hexafluorofosfato de O-(benzotriazol-1-il)-N,N,N',N'-tetrametilurônio (HBTU) ou hexafluorofosfato de (1-ciano-2-etóxi-2- oxoetilidenaminóxi)dimetilamino-morfolino-carbênio (COMU). Ésteres carboxílicos ativados 4-1 também podem ser preparados a partir de ácidos carboxílicos in situ com um sal de fosfônio, tal como hexa- fluorofosfato de benzotriazol-1-il-oxitripirrolidinofosfônio (PyBop). Ésteres carboxílicos ativados 4-1 também podem ser preparados a partir de ácidos carboxílicos in situ com um reagente de acoplamento, tal como 1-(3-dimetilamino propil)-3-etilcarbodi-imida, ou diciclo- hexilcarbodi-imida, na presença de um triazol, tal como hidroxiben- zotriazoLmonohidratado (HOBt) ou 1-hidróxi-7-azabenzotriazol (HOAt). O-Acilisoureias podem ser preparadas com uma carbodi- imida desidratante, tal como 1-(3-dimetilamino propil)-3-etilcarbodi- imida ou diciclo-hexilcarbodi-imida. Ésteres carboxílicos ativados 4-1 também podem ser preparados a partir de ácidos carboxílicos in situ com um reagente de acoplamento, tal como hexafluorofosfato de 2- cloro-1,3-dimetilimidazolidínio (CIP), na presença de um triazol, tal como hidroxibenzotriazoLmonohidratado (HOBt) ou 1-hidróxi-7- azabenzotriazol (HOAt). Ésteres carboxílicos ativados 4-1 também podem ser preparados a partir de ácidos carboxílicos in situ com um reagente de acoplamento, tal como 2,4,6-trióxido de 2,4,6-tripropil- 1,3,5,2,4,6-trioxatrifosfinano (T3P®) na presença de uma base, tal como piridina.Esquema 4

Figure img0015
[00078] Activated carboxylic acids 4-1 can be an acid halide, such as an acid chloride, an acid bromide or an acid fluoride; a carboxylic ester such as a para-nitrophenyl ester, a pentafluorophenyl ester, an ethyl (hydroxyiminium)cyanoacetate ester, a methyl ester, an ethyl ester, a benzyl ester, an N-hydroxysuccinimidyl ester, a hydroxybenzotriazol-1 -yl ester or a hydroxypyridyltriazol-1-yl ester; an O-acyl isourea; an acid anhydride; or a thioester. Acid chlorides can be prepared from the corresponding carboxylic acids by treatment with a dehydrating chlorinating reagent such as oxalyl chloride or thionyl chloride. Activated carboxylic esters 4-1 can be prepared from carboxylic acids in situ with a uronium salt such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole 3-oxide hexafluorophosphate[4 ,5-b]pyridinium (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or (1-cyano-2-ethoxy-2-hexafluorophosphate) oxoethylideneaminooxy)dimethylamino-morpholino-carbenium (COMU). Activated carboxylic esters 4-1 can also be prepared from carboxylic acids in situ with a phosphonium salt such as benzotriazol-1-yl-oxytripyrrolidinephosphonium hexafluorophosphate (PyBop). Activated carboxylic esters 4-1 can also be prepared from carboxylic acids in situ with a coupling reagent, such as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide, or dicyclohexylcarbodiimide, in the presence of a triazole, such as hydroxybenzotriazoL monohydrate (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt). O-Acylisoureas can be prepared with a dehydrating carbodiimide, such as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide or dicyclohexylcarbodiimide. Activated carboxylic esters 4-1 can also be prepared from carboxylic acids in situ with a coupling reagent such as 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP) in the presence of a triazole such as hydroxybenzotriazol monohydrate ( HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt). Activated carboxylic esters 4-1 may also be prepared from carboxylic acids in situ with a coupling reagent such as 2,4,6-trioxide 2,4,6-tripropyl-1,3,5,2,4 ,6-trioxatriphosphinan (T3P®) in the presence of a base such as pyridine.
Figure img0015

[00079] Ciclopropil amidas 5-3, em que R , R , R , R , R , R , R , R8 9 1 10 11 12 13 14 2, R , Q , R , R , R , R , R e Q são conforme divulgados anteriormente e X é (C1-C4)haloalquil ou (C1-C4)alquil(C1-C4)alcóxi, podem ser preparados pelo tratamento de aminas 5-1, em que R1, R2, R3, R4, R5 6 7 8 9 1 10 11 12 13 14 2, R , R , R , R , Q , R , R , R , R , R e Q são conforme divulgados anteriormente e ácidos carboxílicos ativados 5-2, em que A é um grupo de ativação e X é (C1-C4)alquila, (C1-C4)haloalquil ou (C1-C4) alquil(C1-C4)alcóxi, com uma base, como trietilamina, diisopropiletila- mina, 4-metilmorfolina ou 4-dimetilaminopiridina em um solvente apró- tico anidro como diclorometano, tetra-hidrofurano, 1,2-dicloroetano, dimetilformamida ou qualquer combinação destes, em temperaturas entre cerca de 0°C e cerca de 120°C (Esquema 5, etapa a).[00079] Cyclopropyl amides 5-3, wherein R , R , R , R , R , R , R , R8 9 1 10 11 12 13 14 2 , R , Q , R , R , R , R , R and Q are as disclosed above and X is (C1-C4)haloalkyl or (C1-C4)alkyl(C1-C4)alkoxy, can be prepared by treating amines 5-1, where R1, R2, R3, R4, R5 6 7 8 9 1 10 11 12 13 14 2, R , R , R , R , Q , R , R , R , R , R and Q are as previously disclosed and activated carboxylic acids 5-2, where A is a group of activation and X is (C1-C4)alkyl, (C1-C4)haloalkyl or (C1-C4)alkyl(C1-C4)alkoxy, with a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine or 4-dimethylaminopyridine in an anhydrous aprotic solvent such as dichloromethane, tetrahydrofuran, 1,2-dichloroethane, dimethylformamide or any combination thereof, at temperatures between about 0°C and about 120°C (Scheme 5, step a).

[00080] Ácidos carboxílicos ativados 5-2 podem ser um haleto de ácido, tal como um cloreto de ácido, um brometo de ácido ou um fluo- reto de ácido; um éster carboxílico, tal como um para-nitrofenil éster, um pentafluorofenil éster, um éster de (hidróxi-imínio)cianoacetato de etila, um metil éster, um etil éster, um benzil éster, um N- hidroxissuccinimidil éster, um hidroxibenzotriazol-1-il ester ou um hi- droxipiridiltriazol-1-il éster; uma O-acilisoureia; um anidrido de ácido; ou um tioéster. Cloretos de ácidos podem ser preparados a partir dos ácidos carboxílicos correspondentes através de tratamento com um reagente de cloração desidratante, tal como cloreto de oxalila ou cloreto de tionila. Ésteres carboxílicos ativados 5-2 podem ser preparados a partir de ácidos carboxílicos in situ com um sal de urônio, tal como 3-óxido hexafluorofosfato de 1- [bis(dimetilamino)metileno]-1H- 1,2,3-triazolo[4,5-b]piridínio (HATU), hexafluorofosfato de O- (benzotriazol-1-il)-N,N,N',N'-tetrametilurônio (HBTU) ou hexafluorofos- fato de (1-ciano-2-etóxi-2-oxoetilidenaminóxi)dimetilamino-morfolino- carbênio (COMU). Ésteres carboxílicos ativados 5-2 também podem ser preparados a partir de ácidos carboxílicos in situ com um sal de fosfônio, tal como hexafluorofosfato de benzotriazol-1-il- oxitripirrolidinofosfônio (PyBop). Ésteres carboxílicos ativados 5-2 também podem ser preparados a partir de ácidos carboxílicos in situ com um reagente de acoplamento, tal como 1-(3-dimetilamino propil)- 3-etilcarbodiimida, ou diciclo-hexilcarbodiimida, na presença de um triazol, tal como hidroxibenzotriazol monoidratado (HOBt) ou 1- hidróxi-7-azabenzotriazol (HOAt). O-Acilisoureias podem ser preparadas com uma carbodi-imida desidratante, tal como 1-(3- dimetilamino propil)-3-etilcarbodi-imida ou diciclo-hexilcarbodi-imida. Ésteres carboxílicos ativados 5-2 também podem ser preparados a partir de ácidos carboxílicos in situ com um reagente de acoplamento, tal como hexafluorofosfato de 2-cloro-1,3-dimetilimidazolidínio (CIP), na presença de um triazol, tal como 1-hidróxi-7-azabenzotriazol (HO- At). Ésteres carboxílicos ativados 5-2 também podem ser preparados a partir de ácidos carboxílicos in situ com um reagente de acoplamento, tal como 2,4,6-trióxido de 2,4,6-tripropil-1,3,5,2,4,6-trioxa- trifosfinano (T3P®) na presença de uma base, tal como piridina.Esquema 5

Figure img0016
1245678[00080] Activated carboxylic acids 5-2 can be an acid halide, such as an acid chloride, an acid bromide or an acid fluoride; a carboxylic ester, such as a para-nitrophenyl ester, a pentafluorophenyl ester, an ethyl (hydroxyiminium)cyanoacetate ester, a methyl ester, an ethyl ester, a benzyl ester, an N-hydroxysuccinimidyl ester, a hydroxybenzotriazol-1 -yl ester or a hydroxypyridyltriazol-1-yl ester; an O-acyl isourea; an acid anhydride; or a thioester. Acid chlorides can be prepared from the corresponding carboxylic acids by treatment with a dehydrating chlorinating reagent such as oxalyl chloride or thionyl chloride. Activated carboxylic esters 5-2 can be prepared from carboxylic acids in situ with a uronium salt such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole 3-oxide hexafluorophosphate[4 ,5-b]pyridinium (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or (1-cyano-2-ethoxy-hexafluorophosphate) 2-oxoethylideneaminooxy)dimethylamino-morpholinocarbenium (COMU). Activated carboxylic esters 5-2 can also be prepared from carboxylic acids in situ with a phosphonium salt such as benzotriazol-1-yl-oxytripyrrolidinephosphonium hexafluorophosphate (PyBop). Activated carboxylic esters 5-2 can also be prepared from carboxylic acids in situ with a coupling reagent, such as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide, or dicyclohexylcarbodiimide, in the presence of a triazole, such as as hydroxybenzotriazole monohydrate (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt). O-Acylisoureas can be prepared with a dehydrating carbodiimide, such as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide or dicyclohexylcarbodiimide. Activated carboxylic esters 5-2 can also be prepared from carboxylic acids in situ with a coupling reagent such as 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP) in the presence of a triazole such as 1- hydroxy-7-azabenzotriazole (HO-At). Activated carboxylic esters 5-2 can also be prepared from carboxylic acids in situ with a coupling reagent such as 2,4,6-trioxide 2,4,6-tripropyl-1,3,5,2,4 ,6-trioxa-triphosphinan (T3P®) in the presence of a base such as pyridine.
Figure img0016
1245678

[00081] Ciclopropil amidas 6-3, em que R , R , R , R , R , R , R ,R9 1 10 11 12 13 14 15 16 2, Q , R , R , R , R , R , R , R e Q são conforme divulgados anteriormente, podem ser preparadas pelo tratamento de brometo 1 2 4 5 6 7 8 9 1 10 11 12de arila 6-1, em que R , R , R , R , R , R , R , R , Q , R , R , R , R13, R14, R15, R16 e Q2 são conforme divulgados anteriormente, e (C1-C6) alquenil estanana 6-2 em que cada alquenil pode ser opcionalmente substituído por um ou mais F, com uma fonte de paládio, como dicloreto de bis(trifenilfosfina)paládio(II) em um solvente apró- tico como 1,4-dioxano, em temperaturas entre cerca de 20°C e cerca de 120°C (Esquema 6, etapa a).Esquema 6

Figure img0017
[00081] Cyclopropyl amides 6-3, wherein R , R , R , R , R , R , R ,R9 1 10 11 12 13 14 15 16 2, Q , R , R , R , R , R , R , R and Q are as disclosed above, can be prepared by treating aryl 6-1 bromide 1 2 4 5 6 7 8 9 1 10 11 12, where R , R , R , R , R , R , R , R , Q, R, R, R, R13, R14, R15, R16 and Q2 are as previously disclosed, and (C1-C6) alkenyl stannane 6-2 wherein each alkenyl may be optionally substituted by one or more F, with a source of palladium, such as bis(triphenylphosphine)palladium(II) dichloride in an aprotic solvent such as 1,4-dioxane, at temperatures between about 20°C and about 120°C (Scheme 6, step a). 6
Figure img0017

[00082] Em algumas modalidades, 1-3 pode ser preparado a partir do aldeído α,β-insaturado 7-1, em que R1, R2, R3, R4, R5, R6 e R9 são como previamente. Alguém versado na técnica compreenderá que o composto 7-1 pode ser sintetizado por meio da condensação de Aldol (vide Yoshikawa, M.; Kamei, T. PCT Int. Appl. 2010123006, 2010) de um aldeído e acetaldeído adequadamente substituídos disponíveis comercialmente. O tratamento de 7-1 com um ortoforma- to de alquil (C1-C6) na presença de um ácido cujo pH seja de 0-5, tal como ácido bromídrico, N-bromossuccinimida, ácido clorídrico, N- clorossuccinimida e p-toluenossulfonato de piridínio (PPTS), em um solvente de (C1-C6)alcanol, a uma temperatura de 0°C até a temperatura ambiente e sob pressão ambiente provê o acetal 7-2, em que R1, R2, R3, R4, R5, R6 e R9 são como divulgado previamente e Ra é um (C1-C6)alquil ou Ra e Ra tomados em conjunto podem formar um acetal cíclico (Esquema 7, etapa a). O acetal 7-2 pode ser converti- 1 2345678do em ciclopropil acetal 7-3, em que R , R , R , R , R , R , R , R , R9 e Ra são como divulgado previamente, através do tratamento com uma fonte de carbeno, tal como uma halofórmio, por exemplo, bromofórmio ou clorofórmio, na presença de uma base inorgânica, tal como hidróxido sódio ou de potássio ou carbonato de sódio ou de potássio, e um catalisador de transferência de fase, tal como benzil cloreto de trietilamônio, brometo de (-)-N-dodecil-N-metilefedrínio, brometo de tetrametilamônio, brometo de tetrapropilamônio, tetraflu- oroborato de tetrabutilamônio, cloreto de tetrametilamônio ou hexa- fluorofosfato de tetrabutilamônio, a uma temperatura de cerca da temperatura ambiente até abaixo do ponto de ebulição do halofórmio (Esquema 7, etapa b). Atenção: A etapa B é uma reação exotérmica e se deve exercer controle cuidadoso da exoterma ao se conduzir esta reação. O ciclopropil acetal 7-3 pode ser transformado em alde-1 2345678 9ído 7-4, em que R , R , R , R , R , R , R , R e R são como divulgado previamente, em um solvente polar selecionado do grupo consistindo em acetona, acetonitrila, metanol, etanol, nitrometano, N,N- dimetilformamida, dimetilsulfóxido, acetato de etila, tetra-hidrofurano e 1,4-dioxano, na presença de um ácido mineral aquoso selecionado do grupo consistindo em ácido nítrico, ácido clorídrico, ácido bromí- drico e ácido sulfúrico (Esquema 7, etapa c) à temperatura ambien- 1 2345678te. O ácido ciclopropílico 1-3, em que R , R , R , R , R , R , R , R e R9 são como divulgado previamente, pode ser obtido por oxidação do aldeído 7-4 com oxidantes tais como permanganato de sódio ou permanganato de potássio, ou sob condições de oxidação de Pinnick em um solvente aprótico polar selecionado do grupo consistindo em acetona, acetonitrila, N,N-dimetilformamida, dimetilsulfóxido, acetato de etila, tetra-hidrofurano e 1,4-dioxano, a uma temperatura de cerca de 0°C até cerca da temperatura ambiente (Esquema 7, etapa d). Precauções de segurança padrão devem ser exercidas pois uma exoterma pode ocorrer ao se conduzir esta reação.Esquema 7

Figure img0018
[00082] In some embodiments, 1-3 can be prepared from the α,β-unsaturated aldehyde 7-1, where R1, R2, R3, R4, R5, R6 and R9 are as previously. One of skill in the art will understand that compound 7-1 can be synthesized via Aldol condensation (see Yoshikawa, M.; Kamei, T. PCT Int. Appl. 2010123006, 2010) of a commercially available suitably substituted aldehyde and acetaldehyde. Treatment of 7-1 with an alkyl orthoformate (C1-C6) in the presence of an acid whose pH is 0-5, such as hydrobromic acid, N-bromosuccinimide, hydrochloric acid, N-chlorosuccinimide and p-toluenesulfonate of pyridinium (PPTS), in a solvent of (C1-C6)alkanol, at a temperature of 0°C to room temperature and under ambient pressure provides the 7-2 acetal, where R1, R2, R3, R4, R5 , R6 and R9 are as previously disclosed and Ra is a (C1-C6)alkyl or Ra and Ra taken together can form a cyclic acetal (Scheme 7, step a). Acetal 7-2 can be converted to cyclopropyl acetal 7-3, wherein R , R , R , R , R , R , R , R , R9 and Ra are as previously disclosed, by treatment with a source of carbene, such as a haloform, for example, bromoform or chloroform, in the presence of an inorganic base, such as sodium or potassium hydroxide or sodium or potassium carbonate, and a phase transfer catalyst, such as benzyl chloride triethylammonium bromide, (-)-N-dodecyl-N-methylephedrinium bromide, tetramethylammonium bromide, tetrapropylammonium bromide, tetrabutylammonium tetrafluoroborate, tetramethylammonium chloride or tetrabutylammonium hexafluorophosphate, at a temperature from about room temperature to below the boiling point of haloform (Scheme 7, step b). Attention: Step B is an exothermic reaction and careful control of the exotherm must be exercised when conducting this reaction. Cyclopropyl acetal 7-3 can be transformed into aldehyde-1 2345678 9ido 7-4, wherein R , R , R , R , R , R , R , R and R are as previously disclosed, in a polar solvent selected from the group consisting of acetone, acetonitrile, methanol, ethanol, nitromethane, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, tetrahydrofuran and 1,4-dioxane, in the presence of an aqueous mineral acid selected from the group consisting of nitric acid, acid hydrochloric acid, hydrobromic acid and sulfuric acid (Scheme 7, step c) at room temperature 1,2345678t. Cyclopropyl acid 1-3, wherein R , R , R , R , R , R , R , R and R9 are as previously disclosed, can be obtained by oxidation of aldehyde 7-4 with oxidants such as sodium permanganate or permanganate of potassium, or under Pinnick oxidation conditions in a polar aprotic solvent selected from the group consisting of acetone, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, tetrahydrofuran and 1,4-dioxane, at a temperature of about 0°C to about room temperature (Scheme 7, step d). Standard safety precautions must be exercised as an exotherm may occur when conducting this reaction.
Figure img0018

[00083] Aqueles versados na técnica compreenderão que, em algumas modalidades, o ácido ciclopropílico 1-3, em que R1, R2, R3, R4, R5, R6, R7, R8 e R9 são como divulgado previamente, pode ser resolvido em seus enantiômeros (R,R) e (S,S) por meio de um método conhecido tal como aquele em Kovalenko V. N., Kulinkovich O. G. Tetrahedron: Asymmetry 2011, 22, 26 (Esquema8, etapa a). Esquema 8

Figure img0019
Exemplos[00083] Those skilled in the art will understand that, in some embodiments, cyclopropyl acid 1-3, wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as previously disclosed, can be resolved into its (R,R) and (S,S) enantiomers by a known method such as that in Kovalenko VN, Kulinkovich OG Tetrahedron: Asymmetry 2011, 22, 26 (Scheme 8, step a). Scheme 8
Figure img0019
Examples

[00084] Estes exemplos são para fins ilustrativos e não devem ser interpretados como limitantes desta descrição somente às modalidades divulgadas nestes exemplos.[00084] These examples are for illustrative purposes and should not be construed as limiting this description only to the embodiments disclosed in these examples.

[00085] Materiais de partida, reagentes e solventes que foram obtidos a partir de fontes comerciais foram usados sem purificação adicional. Solventes anidros foram comprados como Sure/Seal™ da Aldrich e foram usados como recebidos. Os pontos de fusão foram obtidos em um aparato de ponto de fusão em capilar Thomas Hoover Unimelt ou um OptiMelt Automated Melting Point System de Stanford Research Systems e não são corrigidos. Exemplos de uso de "temperatura ambiente" foram realizados em laboratórios com ambiente controlado, com temperaturas variando entre cerca de 20°C a cerca de 24°C. Moléculas recebem seus nomes conhecidos, nomeadas de acordo com os programas de nomenclatura dentro de ISIS Draw, ChemDraw, ou ACD Nome Pro. Se tais programas forem incapazes de nomear uma molécula, tal molécula será nomeada usando regras de nomenclatura convencionais. Dados espectrais de 1H RMN estão em ppm (δ) e foram registrados a 300, 400, 500 ou 600 MHz; dados espectrais de 13C RMN es- tão em ppm (δ) e foram registrados a 75, 100 ou 150 MHz, e dados espectrais de 19F RMN estão em ppm (δ) e foram registrados a 376 MHz, a menos que indicado de outra forma.Exemplo 1: Preparação de ácido trans-2,2-dicloro-3-(3,5-diclorofenil) ciclopropanocarboxílico (C1)

Figure img0020
[00085] Starting materials, reagents and solvents that were obtained from commercial sources were used without further purification. Anhydrous solvents were purchased as Sure/Seal™ from Aldrich and were used as received. Melting points were obtained on a Thomas Hoover Unimelt capillary melting point apparatus or an OptiMelt Automated Melting Point System from Stanford Research Systems and are uncorrected. Examples of the use of "room temperature" have been carried out in laboratories with a controlled environment, with temperatures ranging from about 20°C to about 24°C. Molecules are given their known names, named according to the naming programs within ISIS Draw, ChemDraw, or ACD Name Pro. If such programs are unable to name a molecule, that molecule will be named using conventional naming rules. 1H NMR spectral data are in ppm (δ) and were recorded at 300, 400, 500 or 600 MHz; 13C NMR spectral data are in ppm (δ) and were recorded at 75, 100 or 150 MHz, and 19F NMR spectral data are in ppm (δ) and were recorded at 376 MHz, unless otherwise indicated .Example 1: Preparation of trans-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxylic acid (C1)
Figure img0020

[00086] Cloreto de rutênio(III) (0,080 g, 0,39 mmol) foi adicionado a uma mistura agitada de trans-1,3-dicloro-5-(-2,2-dicloro-3-(4- metoxifenil)ciclopropil)benzeno (C22) (2,8 g, 7,7 mmol) e periodato de sódio (33 g, 160 mmol) em água:acetato de etila:acetonitrila (8:1:1, 155 mL) a 23°C. A mistura marrom bifásica resultante foi vigorosamente agitada a 23°C por 5 horas. A mistura de reação foi diluída com água (1000 mL) e extraída com diclorometano (4 x 200 mL). As camadas orgânicas combinadas foram secas sobre sulfato de magnésio, filtradas e concentradas. O resíduo foi diluído com uma solução de hidróxido de sódio 1 M, 100 mL) e lavado com éter dietílico (4 x 50 mL). A camada aquosa foi ajustada para pH 2, usando ácido clorídrico concentrado e extraída com diclorometano (3 x 50 mL). As camadas orgânicas combinadas foram secas sobre sulfato de magnésio, filtradas e concentradas para resultar no produto do título como um pó marrom claro (0,78 g, 34%): pf 117 - 120°C; 1H RMN (400 MHz, DMSO-d6) δ 13,38 (br s, 1H), 7,52 - 7,65 (m, 3H), 3,57(d,J = 8,5 Hz, 1H), 3,50 (d,J = 8,5 Hz, 1H); IR (película fina) 3083 (s), 3011 (s), 1731 (s), 1590 (w), 1566 (s), 1448 (w), 1431(m), 1416 (m) cm-1.[00086] Ruthenium(III) chloride (0.080 g, 0.39 mmol) was added to a stirred mixture of trans-1,3-dichloro-5-(-2,2-dichloro-3-(4-methoxyphenyl) cyclopropyl)benzene (C22) (2.8 g, 7.7 mmol) and sodium periodate (33 g, 160 mmol) in water:ethyl acetate:acetonitrile (8:1:1, 155 mL) at 23°C . The resulting brown biphasic mixture was vigorously stirred at 23°C for 5 hours. The reaction mixture was diluted with water (1000 ml) and extracted with dichloromethane (4 x 200 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was diluted with 1M sodium hydroxide solution, 100ml) and washed with diethyl ether (4x50ml). The aqueous layer was adjusted to pH 2 using concentrated hydrochloric acid and extracted with dichloromethane (3x50ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the title product as a light brown powder (0.78 g, 34%): mp 117 - 120°C; 1H NMR (400 MHz, DMSO-d6) δ 13.38 (br s, 1H), 7.52 - 7.65 (m, 3H), 3.57(d,J = 8.5 Hz, 1H), 3.50 (d,J = 8.5 Hz, 1H); IR (thin film) 3083 (s), 3011 (s), 1731 (s), 1590 (w), 1566 (s), 1448 (w), 1431 (m), 1416 (m) cm-1.

[00087] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 1: Ácido trans-2,2-Dicloro-3-(3,4,5-triclorofenil)ciclopropanocarboxílico (C2)

Figure img0021
[00087] The following compounds were prepared in a manner similar to the procedure described in Example 1: trans-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropanecarboxylic acid (C2)
Figure img0021

[00088] Isolado como um pó amarelo (1,5 g, 39%): 1H RMN (400 MHz, CDCl3) δ 7,31 (d, J = 0,7 Hz, 2H), 3,40 (d, J = 8,2 Hz, 1H), 2,86 (d, J = 8,3 Hz, 1H); 13C RMN (101 MHz, CDCl3) δ 171,05, 134,55, 132,44, 131,75, 128,89, 61,18, 39,26, 37,14; ESIMS m/z 333 ([M-H]-).Ácido trans-2,2-Dicloro-3-(3,4-diclorofenil)ciclopropanocarboxílico (C3)

Figure img0022
[00088] Isolated as a yellow powder (1.5 g, 39%): 1H NMR (400 MHz, CDCl 3 ) δ 7.31 (d, J = 0.7 Hz, 2H), 3.40 (d, J = 8.2 Hz, 1H), 2.86 (d, J = 8.3 Hz, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 171.05, 134.55, 132.44, 131.75, 128.89, 61.18, 39.26, 37.14; ESIMS m/z 333 ([MH]-). trans-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropanecarboxylic acid (C3)
Figure img0022

[00089] Isolado como um sólido amarelo pálido (3,2 g, 51%): 1H RMN (400 MHz, CDCl3) δ 7,47 (d, J = 8,3 Hz, 1H), 7,37 (d, J = 1,6 Hz, 1H), 7,12 (ddd, J = 8,3, 2,1, 0,6 Hz, 1H), 3,43 (d, J = 8,3 Hz, 1H), 2,86 (d, J = 8,3 Hz, 1H); 13C RMN (101 MHz, CDCl3) δ 171,52, 132,91, 132,76, 132,29, 130,66, 130,62, 128,02, 61,48, 39,65, 37,13; ESIMS m/z 298 ([M-H]-).Exemplo 2: Preparação de ácido trans-2,2-dicloro-3-(4-(trifluorometil) fenil)ciclopropanocarboxílico (C4)

Figure img0023
[00089] Isolated as a pale yellow solid (3.2 g, 51%): 1H NMR (400 MHz, CDCl 3 ) δ 7.47 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.12 (ddd, J = 8.3, 2.1, 0.6 Hz, 1H), 3.43 (d, J = 8.3 Hz, 1H), 2.86 (d, J = 8.3 Hz, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 171.52, 132.91, 132.76, 132.29, 130.66, 130.62, 128.02, 61.48, 39.65, 37.13; ESIMS m/z 298 ([MH]-).Example 2: Preparation of trans-2,2-dichloro-3-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid (C4)
Figure img0023

[00090] A uma mistura agitada de trans-1-(2,2-dicloro-3-(4-(trifluoro- metil)fenil)ciclopropil)-4-metoxibenzeno (C25) (3,50 g, 9,60 mmol) e periodato de sódio (30,8 g, 144 mmol) em água:acetato de eti- la:acetonitrila (8:1:1, 200 mL) foi adicionado cloreto de rutênio(III) (0,100 g, 0,400 mmol) a 23°C. A mistura resultante foi vigorosamente agitada a 23°C por cerca de 5 horas. A mistura de reação foi diluída com diclorometano e lavada com água. As camadas orgânicas combinadas foram secas sobre sulfato de sódio, filtradas e concentradas. Purificação por cromatografia flash em coluna proveu o composto do título como um sólido esbranquiçado (0,630 g, 38%): pf 100 - 102°C; 1H RMN (400 MHz, DMSO-d6) δ 13,43 (brs, 1H), 7,77 - 7,73 (m, 2H), 7,67 - 7,64 (m, 2H), 3,55 (d, J = 8,8 Hz, 1H), 3,44 (d, J = 8,8 Hz, 1H); ESIMS m/z 347 ([M-H]-).[00090] To a stirred mixture of trans-1-(2,2-dichloro-3-(4-(trifluoromethyl)phenyl)cyclopropyl)-4-methoxybenzene (C25) (3.50 g, 9.60 mmol) ) and sodium periodate (30.8 g, 144 mmol) in water:ethyl acetate:acetonitrile (8:1:1, 200 mL) was added ruthenium(III) chloride (0.100 g, 0.400 mmol) to 23°C. The resulting mixture was vigorously stirred at 23°C for about 5 hours. The reaction mixture was diluted with dichloromethane and washed with water. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by flash column chromatography provided the title compound as an off-white solid (0.630 g, 38%): mp 100 - 102°C; 1H NMR (400 MHz, DMSO-d6) δ 13.43 (brs, 1H), 7.77 - 7.73 (m, 2H), 7.67 - 7.64 (m, 2H), 3.55 ( d, J = 8.8 Hz, 1H), 3.44 (d, J = 8.8 Hz, 1H); ESIMS m/z 347 ([M-H]-).

[00091] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 2:Ácido trans-2,2-Dicloro-3-(3-(trifluorometil)fenil)ciclopropano carboxí- lico (C5)

Figure img0024
[00091] The following compounds were prepared in a manner similar to the procedure described in Example 2: trans-2,2-Dichloro-3-(3-(trifluoromethyl)phenyl)cyclopropane carboxylic acid (C5)
Figure img0024

[00092] Isolado como um sólido esbranquiçado (0,81 g, 33%): pf 86 - 88°C; 1H RMN (400 MHz, DMSO-d6) δ 13,37 (brs, 1H), 7,83 (s, 1H), 7,76 - 7,69 (m, 2H), 7,65 - 7,59 (m, 1H), 3,59 - 3,51 (m, 2H); ESIMS m/z 297 ([M-H]-).Ácido trans-2,2-Dicloro-3-(3-cloro-4-(trifluorometóxi)fenil)ciclopropano- carboxílico (C6)

Figure img0025
[00092] Isolated as an off-white solid (0.81 g, 33%): mp 86 - 88°C; 1H NMR (400 MHz, DMSO-d6) δ 13.37 (brs, 1H), 7.83 (s, 1H), 7.76 - 7.69 (m, 2H), 7.65 - 7.59 ( m, 1H), 3.59 - 3.51 (m, 2H); ESIMS m/z 297 ([MH]-). trans-2,2-Dichloro-3-(3-chloro-4-(trifluoromethoxy)phenyl)cyclopropane-carboxylic acid (C6)
Figure img0025

[00093] Isolado como um sólido esbranquiçado (0,3 g, 19%): pf 134 - 136°C; 1H RMN (400 MHz, DMSO-d6) δ 13,45 (brs, 1H), 7,82 (d, J = 1,6 Hz, 1H), 7,60 - 7,53 (m, 2H), 3,53 - 3,47 (m, 2H); ESIMS m/z 347 ([M-H]-). Ácido trans-2,2-Dicloro-3-(2,4,5-triclorofenil)ciclopropanocarboxílico (C7)

Figure img0026
[00093] Isolated as an off-white solid (0.3 g, 19%): mp 134 - 136°C; 1H NMR (400 MHz, DMSO-d6) δ 13.45 (brs, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.60 - 7.53 (m, 2H), 3 .53 - 3.47 (m, 2H); ESIMS m/z 347 ([MH]-). trans-2,2-Dichloro-3-(2,4,5-trichlorophenyl)cyclopropanecarboxylic acid (C7)
Figure img0026

[00094] Isolado como um sólido esbranquiçado (0,267 g, 18%): pf 189 - 192°C; 1H RMN (400 MHz, DMSO-d6) δ 13,44 (brs, 1H), 8,01 (s, 1H), 7,82 (s, 1H), 3,52 (d, J = 8,2 Hz, 1H), 3,29 (d, J = 8,2 Hz, 1H); ESIMS m/z 333 ([M-H]-).Ácido trans-3-(3,5-bis(trifluorometil)fenil)-2,2-diclorociclopropanocarbo- xílico (C8)

Figure img0027
[00094] Isolated as an off-white solid (0.267 g, 18%): mp 189 - 192°C; 1H NMR (400 MHz, DMSO-d6) δ 13.44 (brs, 1H), 8.01 (s, 1H), 7.82 (s, 1H), 3.52 (d, J = 8.2 Hz , 1H), 3.29 (d, J = 8.2 Hz, 1H); ESIMS m/z 333 ([MH]-).trans-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropanecarboxylic acid (C8)
Figure img0027

[00095] Isolado como um sólido esbranquiçado (0,5 g, 31%): pf 112 - 114°C; 1H RMN (400 MHz, DMSO-d6) δ 13,43 (brs, 1H), 8,22 (s, 2H), 8,08 (s, 1H), 3,80 - 3,71 (m, 2H); ESIMS m/z 365 ([M-H]-).Ácido trans-2,2-dicloro-3-(3,5-dibromofenil)ciclopropanocarboxílico (C9)

Figure img0028
[00095] Isolated as an off-white solid (0.5 g, 31%): mp 112 - 114°C; 1H NMR (400 MHz, DMSO-d6) δ 13.43 (brs, 1H), 8.22 (s, 2H), 8.08 (s, 1H), 3.80 - 3.71 (m, 2H) ; ESIMS m/z 365 ([MH]-). trans-2,2-dichloro-3-(3,5-dibromophenyl)cyclopropanecarboxylic acid (C9)
Figure img0028

[00096] Isolado como um sólido esbranquiçado (0,5 g, 24%): pf 157 - 159°C; 1H RMN (400 MHz, DMSO-d6) δ 13,36 (brs, 1H), 7,81 (d, J = 1,5 Hz, 2H), 7,72 (d, J = 1,5 Hz, 2H), 3,57 - 3,53 (m, 1H), 3,51 - 3,47 (m, 1H); ESIMS m/z 387 ([M-H]-). Ácido trans-2,2-Dicloro-3-(3-cloro-5-(trifluorometil)fenil)ciclopropano- carboxílico (C10)

Figure img0029
[00096] Isolated as an off-white solid (0.5 g, 24%): mp 157 - 159°C; 1H NMR (400 MHz, DMSO-d6) δ 13.36 (brs, 1H), 7.81 (d, J = 1.5 Hz, 2H), 7.72 (d, J = 1.5 Hz, 2H ), 3.57 - 3.53 (m, 1H), 3.51 - 3.47 (m, 1H); ESIMS m/z 387 ([MH]-). trans-2,2-Dichloro-3-(3-chloro-5-(trifluoromethyl)phenyl)cyclopropane-carboxylic acid (C10)
Figure img0029

[00097] Isolado como um sólido esbranquiçado (0,73 g, 28%): pf 113 - 115°C; 1H RMN (400 MHz, DMSO-d6) δ 13,39 (brs, 1H), 7,91 (s, 1H), 7,86 (s, 1H), 7,84 (s, 1H), 3,69 - 3,60 (m, 2H); ESIMS m/z 333 ([M-H]-).Ácido trans-2,2-Dicloro-3-(3,5-dicloro-4-fluorofenil)ciclopropanocarbo- xílico (C11)

Figure img0030
[00097] Isolated as an off-white solid (0.73 g, 28%): mp 113 - 115 °C; 1H NMR (400 MHz, DMSO-d6) δ 13.39 (brs, 1H), 7.91 (s, 1H), 7.86 (s, 1H), 7.84 (s, 1H), 3.69 - 3.60 (m, 2H); ESIMS m/z 333 ([MH]-). trans-2,2-Dichloro-3-(3,5-dichloro-4-fluorophenyl)cyclopropanecarboxylic acid (C11)
Figure img0030

[00098] Isolado como um sólido esbranquiçado (0,539 g, 34%): 1H RMN (400 MHz, DMSO-d6): δ 13,37 (brs, 1H), 7,71 (d, J = 6,4 Hz, 2H), 3,42 (s, 2H); ESIMS m/z 317 ([M-H]-).Ácido trans-3-(4-Bromo-3,5-diclorofenil)-2,2-diclorociclopropanocarbo- xílico (C12)

Figure img0031
[00098] Isolated as an off-white solid (0.539 g, 34%): 1H NMR (400 MHz, DMSO-d6): δ 13.37 (brs, 1H), 7.71 (d, J = 6.4 Hz, 2H), 3.42 (s, 2H); ESIMS m/z 317 ([MH]-). trans-3-(4-Bromo-3,5-dichlorophenyl)-2,2-dichlorocyclopropanecarboxylic acid (C12)
Figure img0031

[00099] Isolado como um sólido esbranquiçado (0,100 g, 10%): 1H RMN (400MHz, DMSO-d6) δ 13,37 (brs, 1H), 7,76 (s, 3H), 3,57 (d, J = 8,8 Hz, 1H), 3,48 (d, J = 8,8 Hz, 1H); ESIMS m/z 377 ([M-H]-). Ácido trans-3-(3-Bromo-5-clorofenil)-2,2-diclorociclopropanocarboxílico (C13)

Figure img0032
[00099] Isolated as an off-white solid (0.100 g, 10%): 1H NMR (400MHz, DMSO-d6) δ 13.37 (brs, 1H), 7.76 (s, 3H), 3.57 (d, J = 8.8 Hz, 1H), 3.48 (d, J = 8.8 Hz, 1H); ESIMS m/z 377 ([MH]-). trans-3-(3-Bromo-5-chlorophenyl)-2,2-dichlorocyclopropanecarboxylic acid (C13)
Figure img0032

[000100] Isolado como um sólido esbranquiçado (0,4 g, 25%): pf 161 - 163°C; 1H RMN (400MHz, DMSO-d6) δ 13,38 (br s, 1H), 7,70 (d, J = 5,3 Hz, 2H), 7,66 - 7,52 (m, 1H), 3,59 - 3,43 (m, 2H); ESIMS m/z 341 ([M-H]-).Ácido trans-2,2-Dicloro-3-(3-cloro-5-fluorofenil)ciclopropanocarboxílico (C14)

Figure img0033
[000100] Isolated as an off-white solid (0.4 g, 25%): mp 161 - 163°C; 1H NMR (400MHz, DMSO-d6) δ 13.38 (br s, 1H), 7.70 (d, J = 5.3 Hz, 2H), 7.66 - 7.52 (m, 1H), 3 .59 - 3.43 (m, 2H); ESIMS m/z 341 ([MH]-). trans-2,2-Dichloro-3-(3-chloro-5-fluorophenyl)cyclopropanecarboxylic acid (C14)
Figure img0033

[000101] Isolado como um sólido esbranquiçado (0,700 g, 25%): pf 138 - 140°C; 1H RMN (400MHz, DMSO-d6) δ 13,38 (brs, 1H), 7,46 (s, 1H), 7,42 (td, J = 2,0, 8,7 Hz, 1H), 7,37 (d, J = 9,8 Hz, 1H), 3,52 (q, J = 8,5 Hz, 2H); ESIMS m/z 281 ([M-H]-).Ácido trans-2,2-Dicloro-3-(4-cloro-3-fluorofenil)ciclopropanocarboxílico (C15)

Figure img0034
[000101] Isolated as an off-white solid (0.700 g, 25%): mp 138 - 140°C; 1H NMR (400MHz, DMSO-d6) δ 13.38 (brs, 1H), 7.46 (s, 1H), 7.42 (td, J = 2.0, 8.7 Hz, 1H), 7. 37 (d, J = 9.8 Hz, 1H), 3.52 (q, J = 8.5 Hz, 2H); ESIMS m/z 281 ([MH]-). trans-2,2-Dichloro-3-(4-chloro-3-fluorophenyl)cyclopropanecarboxylic acid (C15)
Figure img0034

[000102] Isolado como um sólido esbranquiçado (0,500 g, 20%): pf 140 - 142°C; 1H RMN (400MHz, DMSO-d6) δ 13,40 (brs, 1H), 7,59 (m, 1H), 7,55 (d, J = 8,4 Hz, 1H), 7,33 (dd, J = 2,0, 8,4 Hz, 1H), 3,55 - 3,38 (m, 2H); ESIMS m/z 281 ([M-H]-).Ácido trans-2,2-Dicloro-3-(3-cloro-4-fluorofenil)ciclopropanocarboxílico(C16)

Figure img0035
[000102] Isolated as an off-white solid (0.500 g, 20%): mp 140 - 142°C; 1H NMR (400MHz, DMSO-d6) δ 13.40 (brs, 1H), 7.59 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 2.0, 8.4 Hz, 1H), 3.55 - 3.38 (m, 2H); ESIMS m/z 281 ([MH]-). trans-2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropanecarboxylic acid(C16)
Figure img0035

[000103] Isolado como um sólido esbranquiçado (1,0 g, 53%): pf 121 - 123°C; 1H RMN (400 MHz, DMSO-d6) δ 13,35 (brs, 1H), 7,71 (dd, J = 2,0, 7,2 Hz, 1H), 7,53 - 7,35 (m, 2H), 3,50 - 3,41 (m, 2H); ESIMS m/z 281 ([M-H]-).Ácido trans-2,2-Dicloro-3-(3-cloro-5-metilfenil)ciclopropanocarboxílico (C17)

Figure img0036
[000103] Isolated as an off-white solid (1.0 g, 53%): mp 121 - 123°C; 1H NMR (400 MHz, DMSO-d6) δ 13.35 (brs, 1H), 7.71 (dd, J = 2.0, 7.2 Hz, 1H), 7.53 - 7.35 (m, 2H), 3.50 - 3.41 (m, 2H); ESIMS m/z 281 ([MH]-). trans-2,2-Dichloro-3-(3-chloro-5-methylphenyl)cyclopropanecarboxylic acid (C17)
Figure img0036

[000104] Isolado como um sólido esbranquiçado (1,0 g, 42%): pf 124 - 126°C; 1H RMN (400 MHz, DMSO-d6) δ 13,33 (brs, 1H), 7,30 (s, 1H), 7,23 (s, 1H), 7,21 (s, 1H), 3,38 (s, 2H), 2,31 (s, 3H); ESIMS m/z 277 ([M-H]-).Ácido trans-2,2-Dicloro-3-(3,5-dicloro-4-metilfenil)ciclopropanocarboxí- lico (C18)

Figure img0037
[000104] Isolated as an off-white solid (1.0 g, 42%): mp 124 - 126°C; 1H NMR (400 MHz, DMSO-d6) δ 13.33 (brs, 1H), 7.30 (s, 1H), 7.23 (s, 1H), 7.21 (s, 1H), 3.38 (s, 2H), 2.31 (s, 3H); ESIMS m/z 277 ([MH]-). trans-2,2-Dichloro-3-(3,5-dichloro-4-methylphenyl)cyclopropanecarboxylic acid (C18)
Figure img0037

[000105] Isolado como um sólido esbranquiçado (0,8 g, 40%): pf 181 - 183°C; 1H RMN (400 MHz, DMSO-d6) δ 13,40 (s, 1H), 7,56 (s, 2H), 3,53 - 3,50 (m, 1H), 3,46 - 3,43 (m, 1H), 2,40 (s, 3H); ESIMS m/z 311 ([M-H]-). Ácido trans-2,2-Dicloro-3-(3,4-dicloro-5-metilfenil)ciclopropanocarboxí- lico (C19)

Figure img0038
[000105] Isolated as an off-white solid (0.8 g, 40%): mp 181 - 183°C; 1H NMR (400 MHz, DMSO-d6) δ 13.40 (s, 1H), 7.56 (s, 2H), 3.53 - 3.50 (m, 1H), 3.46 - 3.43 ( m, 1H), 2.40 (s, 3H); ESIMS m/z 311 ([MH]-). trans-2,2-Dichloro-3-(3,4-dichloro-5-methylphenyl)cyclopropanecarboxylic acid (C19)
Figure img0038

[000106] Isolado como um sólido esbranquiçado (0,73 g, 45%): pf 157 - 159°C; 1H RMN (400 MHz, DMSO-d6) δ 13,40 (s, 1H), 7,59 (d, J = 2,0 Hz, 1H), 7,44 (d, J = 1,6 Hz, 1H), 3,43 (q, J = 8,5 Hz, 2H), 2,39 (s, 3H); ESIMS m/z 311 ([M-H]-).Ácido trans-2,2-Dicloro-3-(4-(perfluoroetil)fenil)ciclopropanocarboxílico (C20)

Figure img0039
[000106] Isolated as an off-white solid (0.73 g, 45%): mp 157 - 159°C; 1H NMR (400 MHz, DMSO-d6) δ 13.40 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H ), 3.43 (q, J = 8.5 Hz, 2H), 2.39 (s, 3H); ESIMS m/z 311 ([MH]-).trans-2,2-Dichloro-3-(4-(perfluoroethyl)phenyl)cyclopropanecarboxylic acid (C20)
Figure img0039

[000107] Isolado como um sólido esbranquiçado (0,020 g, 10%): pf 116 - 118°C; 1H RMN (300 MHz, CDCl3) δ 7,63 (d, J = 8,1 Hz, 2H), 7,42 (d, J = 8,1 Hz, 2H), 3,53 (d, J = 8,4 Hz, 1H), 2,94 (d, J = 8,4 Hz, 1H); ESIMS m/z 347 ([M-H]-).Ácido trans-2,2-dicloro-3-(4-etoxifenil)ciclopropanocarboxílico (C21)

Figure img0040
[000107] Isolated as an off-white solid (0.020 g, 10%): mp 116 - 118°C; 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 3.53 (d, J = 8 .4 Hz, 1H), 2.94 (d, J = 8.4 Hz, 1H); ESIMS m/z 347 ([MH]-). trans-2,2-dichloro-3-(4-ethoxyphenyl)cyclopropanecarboxylic acid (C21)
Figure img0040

[000108] Isolado como um sólido esbranquiçado (0,025 g, 5%): pf 129 - 130°C; 1H RMN (400 MHz, CDCl3) δ 7,16 (d, J = 8,4 Hz, 2H), 6,88 (d, J = 8,31 Hz, 2H), 4,03 (q, J = 6,8 Hz, 2H), 3,41 (d, J = 8,0 Hz, 1H), 2,81 (d, J = 8,0 Hz, 1H), 1,41 (t, J = 6,8 Hz, 3H); ESIMS m/z 273 ([M-H]-).Exemplo 3: Preparação de trans-1,3-dicloro-5-(2,2-dicloro-3-(4-metoxi-fenil)ciclopropil)benzeno (C22)

Figure img0041
[000108] Isolated as an off-white solid (0.025 g, 5%): mp 129 - 130°C; 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.31 Hz, 2H), 4.03 (q, J = 6 0.8 Hz, 2H), 3.41 (d, J = 8.0 Hz, 1H), 2.81 (d, J = 8.0 Hz, 1H), 1.41 (t, J = 6.8 Hz, 3H); ESIMS m/z 273 ([MH]-).Example 3: Preparation of trans-1,3-dichloro-5-(2,2-dichloro-3-(4-methoxy-phenyl)cyclopropyl)benzene (C22)
Figure img0041

[000109] Hidróxido de sódio aquoso (50%, 6,8 mL, 130 mmol) foi adicionado a uma solução agitada de (E)-1,3-dicloro-5-(4-metoxiestiril) benzeno (C43) (2,4 g, 8,6 mmol) e cloreto de N-benzil-N,N-dietile- tanamínio (0,20 g, 0,86 mmol) em clorofórmio (14 mL, 170 mmol) a 23°C. A mistura marrom escura bifásica resultante foi agitada vigorosamente a 23°C por 24 horas. A mistura de reação foi diluída com água (200 mL) e extraída com diclorometano (2 x 100 mL). As camadas orgânicas combinadas foram secas sobre sulfato de magnésio, filtradas e concentradas para resultar no produto do título como um óleo marrom (2,8 g, 90%): 1H RMN (400 MHz, CDCl3) δ 7,34 (t, J = 1,8 Hz, 1H), 7,21 - 7,30 (m, 4H), 6,93 (m, 2H), 3,83 (s, 3H), 3,14 (d, J = 8,5 Hz, 1H), 3,08 (d, J = 8,5 Hz, 1H); IR (película fina) 3075 (w), 2934 (w), 2836 (w), 1724 (w), 1640 (w), 1609 (m), 1584 (m), 1568 (s), 1513 (s) cm-1.[000109] Aqueous sodium hydroxide (50%, 6.8 mL, 130 mmol) was added to a stirred solution of (E)-1,3-dichloro-5-(4-methoxystyryl)benzene (C43) (2, 4g, 8.6mmol) and N-benzyl-N,N-diethyltenaminium chloride (0.20g, 0.86mmol) in chloroform (14ml, 170mmol) at 23°C. The resulting dark brown biphasic mixture was stirred vigorously at 23°C for 24 hours. The reaction mixture was diluted with water (200ml) and extracted with dichloromethane (2x100ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the title product as a brown oil (2.8 g, 90%): 1H NMR (400 MHz, CDCl 3 ) δ 7.34 (t, J = 1.8 Hz, 1H), 7.21 - 7.30 (m, 4H), 6.93 (m, 2H), 3.83 (s, 3H), 3.14 (d, J = 8. 5Hz, 1H), 3.08 (d, J = 8.5Hz, 1H); IR (thin film) 3075 (w), 2934 (w), 2836 (w), 1724 (w), 1640 (w), 1609 (m), 1584 (m), 1568 (s), 1513 (s) cm -1.

[000110] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 3:trans-1,2,3-Tricloro-5-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)benzeno (C23)

Figure img0042
[000110] The following compounds were prepared in a manner similar to the procedure described in Example 3: trans-1,2,3-Trichloro-5-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)benzene ( C23)
Figure img0042

[000111] Isolado como uma espuma escura (4,7 g, 100%): 1H RMN (400 MHz, CDCI3) δ 7,40 (d, J = 0,6 Hz, 2H), 7,29 - 7,22 (m, 2H), 6,96 - 6,89 (m, 2H), 3,83 (s, 3H), 3,12 (d, J = 8,8 Hz, 1H), 3,06 (d, J = 8,7 Hz, 1H); 13C RMN (101 MHz, CDCl3) δ 159,46, 135,08, 134,23, 130,91, 129,85, 129,16, 125,42, 114,02, 64,67, 55,32, 39,62, 38,48. trans-1,2-Dicloro-4-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)benzeno (Ç24)

Figure img0043
[000111] Isolated as a dark foam (4.7 g, 100%): 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 0.6 Hz, 2H), 7.29 - 7.22 (m, 2H), 6.96 - 6.89 (m, 2H), 3.83 (s, 3H), 3.12 (d, J = 8.8 Hz, 1H), 3.06 (d, J=8.7Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 159.46, 135.08, 134.23, 130.91, 129.85, 129.16, 125.42, 114.02, 64.67, 55.32, 39 .62, 38.48. trans-1,2-Dichloro-4-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)benzene (C24)
Figure img0043

[000112] Isolado como um óleo laranja-avermelhado (7,6 g, 99%): 1H RMN (400 MHz, CDCl3) δ 7,47 (d, J = 4,9 Hz, 1H), 7,45 (bs, 1H), 7,30 - 7,23 (m, 2H), 7,21 (dd, J = 8,2, 1,9 Hz, 1H), 6,96 - 6,90 (m, 2H), 3,83 (s, 3H), 3,11 (app. q, J = 8,8 Hz, 2H); 13C RMN (101 MHz, CDCl3) δ 159,39, 134,90, 132,62, 131,99, 130,90, 130,40, 129,90, 128,33, 125,81, 113,98, 64,94, 55,33, 39,52, 38,75.Exemplo 4: Preparação de trans-1-(2,2-dicloro-3-(4- (trifluorometil)fenil) ciclopropil)-4-metoxibenzeno (C25)

Figure img0044
[000112] Isolated as a reddish-orange oil (7.6 g, 99%): 1H NMR (400 MHz, CDCl 3 ) δ 7.47 (d, J = 4.9 Hz, 1H), 7.45 (bs , 1H), 7.30 - 7.23 (m, 2H), 7.21 (dd, J = 8.2, 1.9 Hz, 1H), 6.96 - 6.90 (m, 2H), 3.83 (s, 3H), 3.11 (app. q, J = 8.8 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 159.39, 134.90, 132.62, 131.99, 130.90, 130.40, 129.90, 128.33, 125.81, 113.98, 64 .94, 55.33, 39.52, 38.75. Example 4: Preparation of trans-1-(2,2-dichloro-3-(4-(trifluoromethyl)phenyl)cyclopropyl)-4-methoxybenzene (C25)
Figure img0044

[000113] A uma solução agitada de (E)-1-metóxi-4-(4- (trifluorometil) estiril)benzeno (C46) (4,00 g, 14,0 mmol) e cloreto de N-benzil-N,N-dietiletanamínio (0,320 g, 14,0 mmol) em clorofórmio (23,1 g, 288 mmol), foi adicionado hidróxido de sódio aquoso (50%, 8,64 g, 216 mmol) em água (17 mL) a 23°C, e a mistura resultante foi agitada vigorosamente a 23°C por 16 horas. A mistura de reação foi diluída com água e extraída com diclorometano. As camadas or-gânicas combinadas foram secas sobre sulfato de sódio, filtradas e concentradas. A purificação por cromatografia flash em coluna proveu o composto do título como um sólido esbranquiçado (3,70 g, 68%): 1H RMN (300 MHz, CDCl3) δ 7,65 (d, J = 8,4 Hz, 2H), 7,49 (d, J = 8,4 Hz, 2H), 7,29 (d, J = 8,4 Hz, 2H), 6,94 (d, J = 8,4 Hz, 2H), 3,83 (s, 3H), 3,19 (s, 2H); ESIMS m/z 361 ([M+H]+).[000113] To a stirred solution of (E)-1-methoxy-4-(4-(trifluoromethyl)styryl)benzene (C46) (4.00 g, 14.0 mmol) and N-benzyl-N chloride, N-diethylethanaminium (0.320 g, 14.0 mmol) in chloroform (23.1 g, 288 mmol), was added aqueous sodium hydroxide (50%, 8.64 g, 216 mmol) in water (17 mL) at 23°C. °C, and the resulting mixture was stirred vigorously at 23 °C for 16 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by flash column chromatography provided the title compound as an off-white solid (3.70 g, 68%): 1H NMR (300 MHz, CDCl 3 ) δ 7.65 (d, J = 8.4 Hz, 2H) , 7.49 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 3 .83 (s, 3H), 3.19 (s, 2H); ESIMS m/z 361 ([M+H]+).

[000114] Os seguintes compostos foram preparados de maneira semelhante ao procedimento descrito no Exemplo 4: trans-1-(2,2-Dicloro-3-(4-metoxifenil)ciclopropil)-3-(trifluorometil)benzeno (C26)

Figure img0045
[000114] The following compounds were prepared in a similar manner to the procedure described in Example 4: trans-1-(2,2-Dichloro-3-(4-methoxyphenyl)cyclopropyl)-3-(trifluoromethyl)benzene (C26)
Figure img0045

[000115] Isolado como um líquido marrom (3,5 g, 67%): 1H RMN (300 MHz, CDCI3) δ 7,62 - 7,50 (m, 4H), 7,29 (d, J = 9,0 Hz, 2H), 6,94 (d, J = 9,0 Hz, 2H), 7,35 - 7,25 (m, 3H), 7,97 - 6,88 (m, 1H), 3,83 (s, 3H), 3,19 (m, 2H); ESIMS m/z 361 ([M+H]+).trans-2-Cloro-4-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)-1- (trifluorometóxi)benzeno (C27)

Figure img0046
[000115] Isolated as a brown liquid (3.5 g, 67%): 1H NMR (300 MHz, CDCl 3 ) δ 7.62 - 7.50 (m, 4H), 7.29 (d, J = 9, 0Hz, 2H), 6.94 (d, J = 9.0Hz, 2H), 7.35 - 7.25 (m, 3H), 7.97 - 6.88 (m, 1H), 3. 83 (s, 3H), 3.19 (m, 2H); ESIMS m/z 361 ([M+H]+).trans-2-Chloro-4-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)-1-(trifluoromethoxy)benzene (C27)
Figure img0046

[000116] Isolado como um sólido esbranquiçado (2,5 g, 65%): 1H RMN (400 MHz, CDCl3) δ 7,57 (d, J = 2,0 Hz, 1H), 7,44 (d, J = 8,8 Hz, 1H), 7,35 - 7,25 (m, 3H), 7,97 - 6,88 (m, 1H), 3,84 (s, 3H), 3,15 - 3,05 (m, 2H); ESIMS m/z 411 ([M+H]+).trans-1,2,4-Tricloro-5-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)benzeno (C28)

Figure img0047
[000116] Isolated as an off-white solid (2.5 g, 65%): 1H NMR (400 MHz, CDCl 3 ) δ 7.57 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.35 - 7.25 (m, 3H), 7.97 - 6.88 (m, 1H), 3.84 (s, 3H), 3.15 - 3. 05 (m, 2H); ESIMS m/z 411 ([M+H]+).trans-1,2,4-Trichloro-5-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)benzene (C28)
Figure img0047

[000117] Isolado como um líquido marrom (2,0 g, 58%): EIMS m/z 394 ([M]+).trans-1-(2,2-Dicloro-3-(4-metoxifenil)ciclopropil)-3,5-bis(trifluorometil) benzeno (C29)

Figure img0048
[000117] Isolated as a brown liquid (2.0 g, 58%): EIMS m/z 394 ([M]+).trans-1-(2,2-Dichloro-3-(4-methoxyphenyl)cyclopropyl) -3,5-bis(trifluoromethyl)benzene (C29)
Figure img0048

[000118] Isolado como um líquido marrom (3,0 g, 61%): EIMS m/z 428 ([M]+).trans-1,3-Dibromo-5-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)benzeno(C30)

Figure img0049
[000118] Isolated as a brown liquid (3.0 g, 61%): EIMS m/z 428 ([M]+).trans-1,3-Dibromo-5-(2,2-dichloro-3-( 4-methoxyphenyl)cyclopropyl)benzene(C30)
Figure img0049

[000119] Isolado como um líquido marrom (3,0 g, 57%): 1H RMN (300 MHz, CDCl3) δ 7,64 (s, 1H), 7,45 (s, 2H), 7,25 (d, J = 9,0 Hz, 2H), 6,92 (d, J = 9,0 Hz, 1H), 3,83 (s, 3H), 3,15 - 3,05 (m, 2H); ESIMS m/z 453 ([M+H]+).trans-1-Cloro-3-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)-5-(trifluorome- til)benzeno (C31)

Figure img0050
[000119] Isolated as a brown liquid (3.0 g, 57%): 1H NMR (300 MHz, CDCl 3 ) δ 7.64 (s, 1H), 7.45 (s, 2H), 7.25 (d , J = 9.0 Hz, 2H), 6.92 (d, J = 9.0 Hz, 1H), 3.83 (s, 3H), 3.15 - 3.05 (m, 2H); ESIMS m/z 453 ([M+H]+).trans-1-Chloro-3-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)-5-(trifluoromethyl)benzene (C31)
Figure img0050

[000120] Isolado como um sólido marrom (4,0 g, 74%): 1H RMN (300 MHz, CDCl3) δ 7,64 (s, 1H), 7,45 (s, 1H), 7,42 (s, 1H), 7,26 (d, J = 9,0 Hz, 2H), 6,93 (d, J = 9,0 Hz, 1H), 3,83 (s, 3H), 3,15 - 3,05 (m, 2H); ESIMS m/z 395 ([M+H]+).trans-1,3-Dicloro-5-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)-2-fluoro- benzeno (C32)

Figure img0051
[000120] Isolated as a brown solid (4.0 g, 74%): 1H NMR (300 MHz, CDCl 3 ) δ 7.64 (s, 1H), 7.45 (s, 1H), 7.42 (s , 1H), 7.26 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 1H), 3.83 (s, 3H), 3.15 - 3 .05 (m, 2H); ESIMS m/z 395 ([M+H]+).trans-1,3-Dichloro-5-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)-2-fluoro-benzene (C32)
Figure img0051

[000121] Isolado como um sólido marrom (1,6 g, 54%): 1H RMN (300 MHz, CDCl3) δ 7,32 (d, J = 6,0 Hz, 2H), 7,30 (d, J = 9,0 Hz, 1H), 6,93 (d, J = 9,0 Hz, 1H), 3,83 (s, 3H), 3,12 - 3,05 (m, 2H); ESIMS m/z 297 ([M+H]+).trans-2-Bromo-1,3-dicloro-5-(2,2-dicloro-3-(4-metoxifenil)ciclopropil) benzeno (C33)

Figure img0052
[000121] Isolated as a brown solid (1.6 g, 54%): 1H NMR (300 MHz, CDCl3) δ 7.32 (d, J = 6.0 Hz, 2H), 7.30 (d, J = 9.0 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H), 3.83 (s, 3H), 3.12 - 3.05 (m, 2H); ESIMS m/z 297 ([M+H]+).trans-2-Bromo-1,3-dichloro-5-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)benzene (C33)
Figure img0052

[000122] Isolado como um sólido esbranquiçado (1,5 g, 44%): 1H RMN (300 MHz, CDCl3) δ 7,36 (d, J = 9,0 Hz, 2H), 7,20 (s, 2H), 6,93 (d, J = 9,0 Hz, 2H), 3,83 (s, 3H), 3,15 - 3,05 (m, 2H); ESIMS m/z 439 ([M+H]+).trans-1-Bromo-3-cloro-5-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)ben- zeno (C34)

Figure img0053
[000122] Isolated as an off-white solid (1.5 g, 44%): 1H NMR (300 MHz, CDCl 3 ) δ 7.36 (d, J = 9.0 Hz, 2H), 7.20 (s, 2H) ), 6.93 (d, J = 9.0 Hz, 2H), 3.83 (s, 3H), 3.15 - 3.05 (m, 2H); ESIMS m/z 439 ([M+H]+).trans-1-Bromo-3-chloro-5-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)benzene (C34)
Figure img0053

[000123] Isolado como um sólido esbranquiçado (2,5 g, 50%): 1H RMN (400 MHz, CDCI3) δ 7,49 (s, 1H), 7,30 (s, 1H), 7,28 - 7,24 (m, 3H), 6,92 (d, J = 8,0 Hz, 2H), 3,92 (s, 3H), 3,01 (q, J = 8,8 Hz, 2H); ESIMS m/z 405 ([M+H]+).trans-1-Cloro-3-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)-5-fluorobenze- no (C35)

Figure img0054
[000123] Isolated as an off-white solid (2.5 g, 50%): 1H NMR (400 MHz, CDCl 3 ) δ 7.49 (s, 1H), 7.30 (s, 1H), 7.28 - 7 .24 (m, 3H), 6.92 (d, J = 8.0 Hz, 2H), 3.92 (s, 3H), 3.01 (q, J = 8.8 Hz, 2H); ESIMS m/z 405 ([M+H]+).trans-1-Chloro-3-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)-5-fluorobenzene (C35)
Figure img0054

[000124] Isolado como um líquido marrom (3,5 g, 67%): ESIMS m/z 345 ([M+H]+).trans-1-Cloro-4-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)-2-fluoroben- zeno (C36)

Figure img0055
[000124] Isolated as a brown liquid (3.5 g, 67%): ESIMS m/z 345 ([M+H]+).trans-1-Chloro-4-(2,2-dichloro-3-( 4-methoxyphenyl)cyclopropyl)-2-fluorobenzene (C36)
Figure img0055

[000125] Isolado como um sólido esbranquiçado (2,5 g, 65%):ESIMS m/z 345 ([M+H]+).trans-2-Cloro-4-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)-1-fluorobenze- no (C37)

Figure img0056
[000125] Isolated as an off-white solid (2.5 g, 65%):ESIMS m/z 345 ([M+H]+).trans-2-Chloro-4-(2,2-dichloro-3-( 4-methoxyphenyl)cyclopropyl)-1-fluorobenzene (C37)
Figure img0056

[000126] Isolado como um líquido marrom (2,0 g, 58%): ESIMS m/z 345 ([M+H]+).trans-1-Cloro-3-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)-5-metilbenzeno (C38)

Figure img0057
[000126] Isolated as a brown liquid (2.0 g, 58%): ESIMS m/z 345 ([M+H]+).trans-1-Chloro-3-(2,2-dichloro-3-( 4-methoxyphenyl)cyclopropyl)-5-methylbenzene (C38)
Figure img0057

[000127] Isolado como um sólido esbranquiçado (3,0 g, 47%): 1H RMN (400 MHz, CDCl3) δ 7,27 (d, J = 8,8 Hz, 2H), 7,14 (s, 2H), 7,06 (s, 1H), 6,92 (d, J = 8,8 Hz, 2H), 3,82 (s, 3H), 3,10 (q, J = 8,8 Hz, 2H), 2,36 (s, 3H); ESIMS m/z 341 ([M+H]+).trans-1,3-Dicloro-5-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)-2-metilben- zeno (C39)

Figure img0058
[000127] Isolated as an off-white solid (3.0 g, 47%): 1H NMR (400 MHz, CDCl 3 ) δ 7.27 (d, J = 8.8 Hz, 2H), 7.14 (s, 2H) ), 7.06 (s, 1H), 6.92 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 3.10 (q, J = 8.8 Hz, 2H ), 2.36 (s, 3H); ESIMS m/z 341 ([M+H]+).trans-1,3-Dichloro-5-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)-2-methylbenzene (C39)
Figure img0058

[000128] Isolado como um líquido marrom (2,5 g, 80%): 1H RMN (400 MHz, CDCl3) δ 7,25 (d, J = 8,0 Hz, 2H), 7,17 (d, J = 8,8 Hz, 1H), 6,92 (d, J = 8,0 Hz, 2H), 6,88 (d, J = 8,8 Hz, 1H), 3,82 (s, 3H),3,12 - 3,03 (m, 2H), 2,47 (s, 3H); ESIMS m/z 375 ([M+H]+). trans-1,2-Dicloro-5-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)-3-metilben- zeno (C40)

Figure img0059
[000128] Isolated as a brown liquid (2.5 g, 80%): 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.8 Hz, 1H), 3.82 (s, 3H), 3.12 - 3.03 (m, 2H), 2.47 (s, 3H); ESIMS m/z 375 ([M+H]+). trans-1,2-Dichloro-5-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)-3-methylbenzene (C40)
Figure img0059

[000129] Isolado como um líquido marrom (4,0 g, 90%): ESIMS m/z 375 ([M+H]+).trans-1-(2,2-Dicloro-3-(4-(perfluoroetil)fenil)ciclopropil)-4-metoxiben- zeno (C41)

Figure img0060
[000129] Isolated as a brown liquid (4.0 g, 90%): ESIMS m/z 375 ([M+H]+).trans-1-(2,2-Dichloro-3-(4-(perfluoroethyl) )phenyl)cyclopropyl)-4-methoxybenzene (C41)
Figure img0060

[000130] Isolado como um sólido esbranquiçado (0,5 g, 46%): 1H RMN (400 MHz, CDCI3) δ 7,60 - 7,50 (m, 4H), 7,47 (d, J = 8,0 Hz, 2H), 6,92 (d, J = 8,0 Hz, 2H), 3,82 (s, 3H), 3,20 (s, 2H); ESIMS m/z 411 ([M+H]+).trans-4,4'-(3,3-Diclorociclopropano-1,2-di-il)bis(etoxibenzeno) (C42)

Figure img0061
[000130] Isolated as an off-white solid (0.5 g, 46%): 1H NMR (400 MHz, CDCl 3 ) δ 7.60 - 7.50 (m, 4H), 7.47 (d, J = 8. 0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 3.82 (s, 3H), 3.20 (s, 2H); ESIMS m/z 411 ([M+H]+).trans-4,4'-(3,3-Dichlorocyclopropane-1,2-di-yl)bis(ethoxybenzene) (C42)
Figure img0061

[000131] Isolado como um sólido esbranquiçado (1,5 g, 45%): 1H RMN (400 MHz, CDCl3) δ 7,27 (d, J = 8,0 Hz, 4H), 6,90 (d, J = 8,0 Hz, 4H), 4,04 (q, J = 6,8 Hz, 4H), 3,09 (s, 2H), 1,42 (t, J = 6,8 Hz, 6H); ESIMS m/z 351 ([M+H]+).Exemplo 5: Preparação de (E)-1,3-dicloro-5-(4-metoxiestiril)benzeno ÍÇ43)

Figure img0062
[000131] Isolated as an off-white solid (1.5 g, 45%): 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.0 Hz, 4H), 6.90 (d, J = 8.0 Hz, 4H), 4.04 (q, J = 6.8 Hz, 4H), 3.09 (s, 2H), 1.42 (t, J = 6.8 Hz, 6H); ESIMS m/z 351 ([M+H]+). Example 5: Preparation of (E)-1,3-dichloro-5-(4-methoxystyryl)benzene (C43)
Figure img0062

[000132] Pó de metóxido de sódio (98%, 0,63 g, 11 mmol) foi adicionado a uma solução agitada de 3,5-diclorobenzaldeído (2,0 g, 11 mmol) e 4-metoxibenzilfosfonato de dietila (2,0 mL, 11 mmol) em N,N-dimetilformamida seca (38 mL) a 23°C. A mistura azul escura heterogênea resultante foi aquecida a 80°C, resultando em uma mistura marrom escura, e agitada por 24 horas. A mistura de reação resfriada foi diluída com água (500 mL) e extraída com éter dietílico (3 x 100 mL). As camadas orgânicas combinadas foram diluídas com hexano (150 mL) e lavadas com água (300 mL). A camada orgânica foi seca sobre sulfato de magnésio, filtrada e concentrada para resultar no produto do título como um óleo marrom claro (2,4 g, 75%): 1H RMN (400 MHz, CDCl3) δ 7,44 (m, 2H), 7,34 (d, J = 2 Hz, 2H), 7,20 (t, J = 2 Hz, 1H), 7,06 (d, J = 16,5 Hz, 1H), 6,91 (m, 2H), 6,82 (d, J = 16,5 Hz, 1H), 3,84 (s, 3H); IR (película fina) 2934 (w), 2835 (w), 1724 (w), 1637 (w), 1605 (m), 1581 (m), 1558 (m), 1511 (s) cm-1.[000132] Sodium methoxide powder (98%, 0.63 g, 11 mmol) was added to a stirred solution of 3,5-dichlorobenzaldehyde (2.0 g, 11 mmol) and diethyl 4-methoxybenzylphosphonate (2, 0 mL, 11 mmol) in dry N,N-dimethylformamide (38 mL) at 23°C. The resulting heterogeneous dark blue mixture was heated to 80°C, resulting in a dark brown mixture, and stirred for 24 hours. The cooled reaction mixture was diluted with water (500 ml) and extracted with diethyl ether (3 x 100 ml). The combined organic layers were diluted with hexane (150 ml) and washed with water (300 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to give the title product as a light brown oil (2.4 g, 75%): 1H NMR (400 MHz, CDCl 3 ) δ 7.44 (m, 2H ), 7.34 (d, J = 2 Hz, 2H), 7.20 (t, J = 2 Hz, 1H), 7.06 (d, J = 16.5 Hz, 1H), 6.91 ( m, 2H), 6.82 (d, J = 16.5 Hz, 1H), 3.84 (s, 3H); IR (thin film) 2934 (w), 2835 (w), 1724 (w), 1637 (w), 1605 (m), 1581 (m), 1558 (m), 1511 (s) cm-1.

[000133] Os seguintes compostos foram preparados de maneira semelhante ao procedimento descrito no Exemplo 5:(E)-1,2,3-Tricloro-5-(4-metoxiestiril)benzeno (C44)

Figure img0063
[000133] The following compounds were prepared in a similar manner to the procedure described in Example 5: (E)-1,2,3-Trichloro-5-(4-methoxystyryl)benzene (C44)
Figure img0063

[000134] Isolado como um sólido esbranquiçado (3,7 g, 31%): 1H RMN (400 MHz, CDCI3) δ 7,49 - 7,46 (m, 2H), 7,47 - 7,39 (m, 2H), 7,04 (d, J = 16,3 Hz, 1H), 6,93 - 6,89 (m, 2H), 6,78 (d, J = 16,3 Hz, 1H), 3,84 (s, 3H); 13C RMN (101 MHz, CDCl3) δ 159,46, 135,08, 134,23, 130,91, 129,85, 129,16, 125,42, 114,02, 64,67, 55,32, 39,62, 38,48; EIMS m/z 313 ([M]+). (E)-1,2-Dicloro-4-(4-metoxiestiril)benzeno (C45)

Figure img0064
[000134] Isolated as an off-white solid (3.7 g, 31%): 1H NMR (400 MHz, CDCl 3 ) δ 7.49 - 7.46 (m, 2H), 7.47 - 7.39 (m, 2H), 7.04 (d, J = 16.3 Hz, 1H), 6.93 - 6.89 (m, 2H), 6.78 (d, J = 16.3 Hz, 1H), 3. 84 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 159.46, 135.08, 134.23, 130.91, 129.85, 129.16, 125.42, 114.02, 64.67, 55.32, 39 .62, 38.48; EIMS m/z 313 ([M]+). (E)-1,2-Dichloro-4-(4-methoxystyryl)benzene (C45)
Figure img0064

[000135] Isolado como um sólido esbranquiçado (6,0 g, 53%): pf 91 - 94°C; 1H RMN (400 MHz, CDCh) δ 7,56 (d, J = 2,0 Hz, 1H), 7,46 - 7,42 (m, 2H), 7,39 (d, J = 8,4 Hz, 1H), 7,29 (dd, J = 8,4, 2,1 Hz, 1H), 7,04 (d, J = 16,2 Hz, 1H), 6,93 - 6,88 (m, 2H), 6,85 (d, J = 16,3 Hz, 1H), 3,84 (s, 3H); 13C RMN (101 MHz, CDCl3) δ 159,75, 137,86, 132,72, 130,58, 130,49, 130,12, 129,33, 127,96, 127,77, 125,37, 123,98, 114,24, 55,35; EIMS m/z 279 ([M]+).Exemplo 6: Preparação de (E)-1-metóxi-4-(4-(trifluorometil)estiril) ben-zeno (C46)

Figure img0065
[000135] Isolated as an off-white solid (6.0 g, 53%): mp 91 - 94°C; 1H NMR (400 MHz, CDCh) δ 7.56 (d, J = 2.0 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.39 (d, J = 8.4 Hz , 1H), 7.29 (dd, J = 8.4, 2.1 Hz, 1H), 7.04 (d, J = 16.2 Hz, 1H), 6.93 - 6.88 (m, 2H), 6.85 (d, J = 16.3 Hz, 1H), 3.84 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 159.75, 137.86, 132.72, 130.58, 130.49, 130.12, 129.33, 127.96, 127.77, 125.37, 123 .98, 114.24, 55.35; EIMS m/z 279 ([M]+).Example 6: Preparation of (E)-1-methoxy-4-(4-(trifluoromethyl)styryl)benzene (C46)
Figure img0065

[000136] A uma solução agitada de dietil 4-metoxibenzil fosfonato (8,89 g, 34,0 mmol) em N,N-dimetilformamida (30 mL), foi adicionado pó de metóxido de sódio (1,86 g, 34,0 mmol). A mistura de reação foi agitada à temperatura ambiente por 1 hora. A mistura de reação foi resfriada a 0°C e 4-(trifluorometil)benzaldeído (5,00 g, 28,0 mmol) em N,N-dimetilformamida (30 mL) foi adicionada gota a gota. A mistura de reação foi agitada a 60°C por 2 horas. A mistura de reação foi vertida em água gelada, filtrada e seca para resultar no composto do título como um sólido esbranquiçado (3,60 g, 80%): 1H RMN (300 MHz, CDCl3) δ 7,61 - 7,52 (m, 4H), 7,47 (d, J = 9,0 Hz, 2H), 7,14 (d, J = 16,5 Hz, 1H), 6,97 (d, J = 16,5 Hz, 1H), 6,91 (d, J = 9,0 Hz, 2H), 3,84 (s, 3H); ESIMS m/z 279 ([M+H]+).[000136] To a stirred solution of diethyl 4-methoxybenzyl phosphonate (8.89 g, 34.0 mmol) in N,N-dimethylformamide (30 mL) was added sodium methoxide powder (1.86 g, 34, 0 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C and 4-(trifluoromethyl)benzaldehyde (5.00 g, 28.0 mmol) in N,N-dimethylformamide (30 mL) was added dropwise. The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was poured into ice water, filtered and dried to give the title compound as an off-white solid (3.60 g, 80%): 1H NMR (300 MHz, CDCl 3 ) δ 7.61 - 7.52 ( m, 4H), 7.47 (d, J = 9.0 Hz, 2H), 7.14 (d, J = 16.5 Hz, 1H), 6.97 (d, J = 16.5 Hz, 1H), 6.91 (d, J = 9.0 Hz, 2H), 3.84 (s, 3H); ESIMS m/z 279 ([M+H]+).

[000137] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 6: (E)-1-(4-Metoxiestiril)-3-(trifluorometil)benzeno (C47)

Figure img0066
[000137] The following compounds were prepared in a manner similar to the procedure described in Example 6: (E)-1-(4-Methoxystyril)-3-(trifluoromethyl)benzene (C47)
Figure img0066

[000138] Isolado como um sólido esbranquiçado (4,0 g, 85%): 1H RMN (400 MHz, CDCh) δ 7,72 (s, 1H), 7,64 (d, J = 6,8 Hz, 1H), 7,50 - 7,44 (m, 4H), 7,12 (d, J = 16,0 Hz, 1H), 6,98 (d, J = 16,0 Hz, 1H), 6,91 (d, J = 8,8 Hz, 2H), 3,84 (s, 3H); ESIMS m/z 279 ([M+H]+).(E)-2-Cloro-4-(4-metoxiestiril)-1-(trifluorometóxi)benzeno (C48)

Figure img0067
[000138] Isolated as an off-white solid (4.0 g, 85%): 1H NMR (400 MHz, CDCh) δ 7.72 (s, 1H), 7.64 (d, J = 6.8 Hz, 1H) ), 7.50 - 7.44 (m, 4H), 7.12 (d, J = 16.0 Hz, 1H), 6.98 (d, J = 16.0 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H); ESIMS m/z 279 ([M+H]+).(E)-2-Chloro-4-(4-methoxystyryl)-1-(trifluoromethoxy)benzene (C48)
Figure img0067

[000139] Isolado: ESIMS m/z 329 ([M+H]+).(E)-1-(4-Metoxiestiril)-3,5-bis(trifluorometil)benzeno (C49)

Figure img0068
[000139] Isolated: ESIMS m/z 329 ([M+H]+).(E)-1-(4-Methoxystyril)-3,5-bis(trifluoromethyl)benzene (C49)
Figure img0068

[000140] Isolado como um sólido esbranquiçado (4,0 g, 56%): 1H RMN (300 MHz, CDCl3) δ 7,88 (s, 2H), 7,70 (s, 1H), 7,49 (d, J = 8,4 Hz, 2H), 7,19 (d, J = 16,5 Hz, 1H), 6,99 (d, J = 16,5 Hz, 1H), 6,92 (d, J = 8,4 Hz, 2H), 3,84 (m, 3H); ESIMS m/z 347 ([M+H]+).(E)-1,3-Dibromo-5-(4-metoxiestiril)benzeno (C50)

Figure img0069
[000140] Isolated as an off-white solid (4.0 g, 56%): 1H NMR (300 MHz, CDCl 3 ) δ 7.88 (s, 2H), 7.70 (s, 1H), 7.49 (d , J = 8.4 Hz, 2H), 7.19 (d, J = 16.5 Hz, 1H), 6.99 (d, J = 16.5 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 3.84 (m, 3H); ESIMS m/z 347 ([M+H]+).(E)-1,3-Dibromo-5-(4-methoxystyryl)benzene (C50)
Figure img0069

[000141] Isolado como um sólido esbranquiçado (2,2 g, 54%): 1H RMN (300 MHz, CDCl3) δ 7,53 (s, 1H), 7,50 (s, 2H), 7,43 (d, J = 9,0 Hz, 2H), 7,05 (d, J = 16,2 Hz, 1H), 6,90 (d, J = 9,0 Hz, 2H), 6,79 (d, J = 16,2 Hz, 1H), 3,80 (s, 3H); ESIMS m/z 367 ([M+H]+).(E)-1-Cloro-3-(4-metoxiestiril)-5-(trifluorometil)benzeno (C51)

Figure img0070
[000141] Isolated as an off-white solid (2.2 g, 54%): 1H NMR (300 MHz, CDCl 3 ) δ 7.53 (s, 1H), 7.50 (s, 2H), 7.43 (d , J = 9.0 Hz, 2H), 7.05 (d, J = 16.2 Hz, 1H), 6.90 (d, J = 9.0 Hz, 2H), 6.79 (d, J = 16.2 Hz, 1H), 3.80 (s, 3H); ESIMS m/z 367 ([M+H]+).(E)-1-Chloro-3-(4-methoxystyryl)-5-(trifluoromethyl)benzene (C51)
Figure img0070

[000142] Isolado como um sólido esbranquiçado (4,3 g, 58%): 1H RMN (300MHz, CDCI3) δ 7,62 (s, 1H), 7,58 (s, 1H), 7,48 - 7,42 (m, 3H), 7,12 (d, J = 16,2 Hz, 1H), 6,95 - 6,85(m, 3H), 3,84 (s, 3H); ESIMS m/z 313 ([M+H]+).(E)-2-Bromo-1,3-dicloro-5-(4-metoxiestiril)benzeno (C52)

Figure img0071
[000142] Isolated as an off-white solid (4.3 g, 58%): 1H NMR (300MHz, CDCl 3 ) δ 7.62 (s, 1H), 7.58 (s, 1H), 7.48 - 7. 42 (m, 3H), 7.12 (d, J = 16.2 Hz, 1H), 6.95 - 6.85(m, 3H), 3.84 (s, 3H); ESIMS m/z 313 ([M+H]+).(E)-2-Bromo-1,3-dichloro-5-(4-methoxystyryl)benzene (C52)
Figure img0071

[000143] Isolado como um sólido esbranquiçado (2,8 g, 40%): 1H RMN (300 MHz, CDCl3) δ 7,46 (s, 2H), 7,43 (d, J = 9,0 Hz, 2H), 7,07 (d, J = 13,5 Hz, 1H), 6,90 (d, J = 9,0 Hz, 1H), 6,73 (d, J = 13,5 Hz, 1H), 3,84 (s, 3H); ESIMS m/z 358 ([M+H]+).(E)-1-Bromo-3-cloro-5-(4-metoxiestiril)benzeno (C53)

Figure img0072
[000143] Isolated as an off-white solid (2.8 g, 40%): 1H NMR (300 MHz, CDCl 3 ) δ 7.46 (s, 2H), 7.43 (d, J = 9.0 Hz, 2H) ), 7.07 (d, J = 13.5 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.73 (d, J = 13.5 Hz, 1H), 3.84 (s, 3H); ESIMS m/z 358 ([M+H]+).(E)-1-Bromo-3-chloro-5-(4-methoxystyryl)benzene (C53)
Figure img0072

[000144] Isolado como um sólido esbranquiçado (4,0 g, 63%): 1H RMN (300 MHz, CDCl3) δ 7,49 (s, 1H), 7,43 (d, J = 8,4 Hz, 2H), 7,38 (s, 1H), 7,35 (s, 1H), 7,05 (d, J = 16,5 Hz, 1H), 6,91 (d, J = 8,4 Hz, 2H), 6,80 (d, J = 16,5 Hz, 1H), 3,82 (s, 3H); ESIMS m/z 323 ([M+H]+). (E)-1-Cloro-3-flúor-5-(4-metoxiestiril)benzeno (C54)

Figure img0073
[000144] Isolated as an off-white solid (4.0 g, 63%): 1H NMR (300 MHz, CDCl 3 ) δ 7.49 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H ), 7.38 (s, 1H), 7.35 (s, 1H), 7.05 (d, J = 16.5 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H ), 6.80 (d, J = 16.5 Hz, 1H), 3.82 (s, 3H); ESIMS m/z 323 ([M+H]+). (E)-1-Chloro-3-fluoro-5-(4-methoxystyryl)benzene (C54)
Figure img0073

[000145] Isolado como um sólido esbranquiçado (5,0 g, 60%): 1H RMN (400 MHz, CDCI3) δ 7,45 (d, J = 8,4 Hz, 2H), 7,10 - 7,0 (m, 3H), 6,96 - 6,80 (m, 4H), 3,80 (s, 3H); ESIMS m/z 263 ([M+H]+).(E)-1-Cloro-2-flúor-4-(4-metoxiestiril)benzeno (C55)

Figure img0074
[000145] Isolated as an off-white solid (5.0 g, 60%): 1H NMR (400 MHz, CDCl 3 ) δ 7.45 (d, J = 8.4 Hz, 2H), 7.10 - 7.0 (m, 3H), 6.96 - 6.80 (m, 4H), 3.80 (s, 3H); ESIMS m/z 263 ([M+H]+).(E)-1-Chloro-2-fluoro-4-(4-methoxystyryl)benzene (C55)
Figure img0074

[000146] Isolado como um sólido esbranquiçado (7,0 g, 84%): 1H RMN (400 MHz, CDCl3) δ 7,44 (d, J = 8,0 Hz, 2H), 7,35 - 7,31 (m, 1H), 7,28 - 7,24 (m, 1H), 7,17 (dd, J = 1,6, 8,0 Hz, 1H), 7,03 (d, J = 16,0 Hz, 1H), 6,90 (d, J = 8,0 Hz, 1H), 7,49 (d, J = 8,0 Hz, 1H), 6,86 (d, J = 16,0 Hz, 1H), 3,82 (s, 3H); ESIMS m/z 263 ([M+H]+).(E)-2-Cloro-1-flúor-4-(4-metoxiestiril)benzeno (C56)

Figure img0075
[000146] Isolated as an off-white solid (7.0 g, 84%): 1H NMR (400 MHz, CDCl 3 ) δ 7.44 (d, J = 8.0 Hz, 2H), 7.35 - 7.31 (m, 1H), 7.28 - 7.24 (m, 1H), 7.17 (dd, J = 1.6, 8.0 Hz, 1H), 7.03 (d, J = 16.0 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 16.0 Hz, 1H), 3.82 (s, 3H); ESIMS m/z 263 ([M+H]+).(E)-2-Chloro-1-fluoro-4-(4-methoxystyryl)benzene (C56)
Figure img0075

[000147] Isolado como um sólido esbranquiçado (6,0 g, 72%): ESIMS m/z 263 ([M+H]+).(E)-1-Cloro-3-(4-metoxiestiril)-5-metilbenzeno (C57)

Figure img0076
[000147] Isolated as an off-white solid (6.0 g, 72%): ESIMS m/z 263 ([M+H]+).(E)-1-Chloro-3-(4-methoxystyril)-5- methylbenzene (C57)
Figure img0076

[000148] Isolado como um sólido esbranquiçado (5,0 g, 60%): 1H RMN (300 MHz, CDCl3) δ 7,44 (d, J = 8,4 Hz, 2H), 7,28 (s, 1H), 7,15 (s, 1H), 7,05 - 7,00 (m, 2H), 6,91 - 6,83 (m, 3H), 3,83 (s, 3H), 2,24 (s, 3H); ESIMS m/z 259 ([M+H]+).(E)-1-Metóxi-4-(4-(perfluoroetil)estiril)benzeno (C58)

Figure img0077
[000148] Isolated as an off-white solid (5.0 g, 60%): 1H NMR (300 MHz, CDCl 3 ) δ 7.44 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H) ), 7.15 (s, 1H), 7.05 - 7.00 (m, 2H), 6.91 - 6.83 (m, 3H), 3.83 (s, 3H), 2.24 ( s, 3H); ESIMS m/z 259 ([M+H]+).(E)-1-Methoxy-4-(4-(perfluoroethyl)styryl)benzene (C58)
Figure img0077

[000149] Isolado como um sólido esbranquiçado (0,5 g, 42%): 1H RMN (400 MHz, CDCl3) δ 7,60 - 7,50 (m, 4H), 7,47 (d, J = 8,8 Hz, 2H),7,15 (d, J = 16,8 Hz, 1H), 6,98 (d, J = 16,8 Hz, 1H), 6,92 (d, J = 8,8 Hz, 2H), 3,82 (s, 3H); ESIMS m/z 329 ([M+H]+).(E)-1,2-bis(4-etoxifenil)eteno (C59)

Figure img0078
[000149] Isolated as an off-white solid (0.5 g, 42%): 1H NMR (400 MHz, CDCl 3 ) δ 7.60 - 7.50 (m, 4H), 7.47 (d, J = 8. 8 Hz, 2H), 7.15 (d, J = 16.8 Hz, 1H), 6.98 (d, J = 16.8 Hz, 1H), 6.92 (d, J = 8.8 Hz , 2H), 3.82 (s, 3H); ESIMS m/z 329 ([M+H]+).(E)-1,2-bis(4-ethoxyphenyl)ethene (C59)
Figure img0078

[000150] Isolado como um sólido esbranquiçado (1,7 g, 34%): 1H RMN (300 MHz, CDCl3) δ 7,40 (d, J = 9,0 Hz, 4H), 6,91 (s, 2H), 6,87 (d, J = 9,0 Hz, 4H), 4,05 (q, J = 6,9 Hz, 4H), 1,42 (t, J = 6,9 Hz, 6H); ESIMS m/z 269 ([M+H]+).Exemplo 7: Preparação de (E)-1,3-dicloro-2-flúor-5-(4-metoxiestiril) benzeno (C60)

Figure img0079
[000150] Isolated as an off-white solid (1.7 g, 34%): 1H NMR (300 MHz, CDCl 3 ) δ 7.40 (d, J = 9.0 Hz, 4H), 6.91 (s, 2H) ), 6.87 (d, J = 9.0 Hz, 4H), 4.05 (q, J = 6.9 Hz, 4H), 1.42 (t, J = 6.9 Hz, 6H); ESIMS m/z 269 ([M+H]+).Example 7: Preparation of (E)-1,3-dichloro-2-fluoro-5-(4-methoxystyryl)benzene (C60)
Figure img0079

[000151] Uma mistura agitada de 5-bromo-1,3-dicloro-2-fluoroben- zeno (2,00 g, 8,20 mmol), 1-metóxi-4-vinilbenzeno (1,32 g, 9,80 mmol), e trietilamina (20 mL) sob argônio foi desgaseificada por 5 minutos. Acetato de paládio(II) (0,0368 g, 0,164 mmol) e 1,1'-bis(difenilfosfino) ferroceno (0,181 g, 0,328 mmol) foram adicionados e a reação foi aquecida a 90°C por 16 horas. A mistura de reação foi vertida em água e extraída com acetato de etila. As camadas orgânicas combinadas foram secas sobre sulfato de sódio, filtradas e concentradas. A purificação por cromatografia flash em coluna proveu o composto do título como um sólido esbranquiçado (1,60 g, 67%): 1H RMN (300 MHz, CDCl3) δ 7,41 (d, J = 8,8 Hz, 2H), 7,31 (s, 1H), 7,37 (s, 1H), 6,96 (d, J = 16,0 Hz, 1H), 6,89 (d, J = 8,8 Hz, 2H), 6,76 (d, J = 16,0 Hz, 1H), 3,84 (s, 3H); ESIMS m/z 297 ([M+H]+).[000151] A stirred mixture of 5-bromo-1,3-dichloro-2-fluorobenzene (2.00 g, 8.20 mmol), 1-methoxy-4-vinylbenzene (1.32 g, 9.80 mmol), and triethylamine (20 mL) under argon was degassed for 5 minutes. Palladium(II) acetate (0.0368 g, 0.164 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (0.181 g, 0.328 mmol) were added and the reaction was heated at 90°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by flash column chromatography provided the title compound as an off-white solid (1.60 g, 67%): 1H NMR (300 MHz, CDCl 3 ) δ 7.41 (d, J = 8.8 Hz, 2H) , 7.31 (s, 1H), 7.37 (s, 1H), 6.96 (d, J = 16.0 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H) , 6.76 (d, J = 16.0 Hz, 1H), 3.84 (s, 3H); ESIMS m/z 297 ([M+H]+).

[000152] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 7:(E)-1,3-Dicloro-5-(4-metoxiestiril)-2-metilbenzeno (C61)

Figure img0080
[000152] The following compounds were prepared in a manner similar to the procedure described in Example 7: (E)-1,3-Dichloro-5-(4-methoxystyryl)-2-methylbenzene (C61)
Figure img0080

[000153] Isolado como um sólido esbranquiçado (2,5 g, 67%): 1H RMN (300 MHz, CDCl3) δ 7,43 (d, J = 8,7 Hz, 2H), 7,38 (s, 2H), 7,02 (d, J = 16,5 Hz, 1H), 6,90 (d, J = 8,7 Hz, 2H), 6,79 (d, J = 16,5 Hz, 1H), 3,82 (s, 3H), 2,42 (s, 3H); ESIMS m/z 293 ([M+H]+).(E)-1,2-Dicloro-5-(4-metoxiestiril)-3-metilbenzeno (C62)

Figure img0081
[000153] Isolated as an off-white solid (2.5 g, 67%): 1H NMR (300 MHz, CDCl 3 ) δ 7.43 (d, J = 8.7 Hz, 2H), 7.38 (s, 2H) ), 7.02 (d, J = 16.5 Hz, 1H), 6.90 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 16.5 Hz, 1H), 3.82 (s, 3H), 2.42 (s, 3H); ESIMS m/z 293 ([M+H]+).(E)-1,2-Dichloro-5-(4-methoxystyryl)-3-methylbenzene (C62)
Figure img0081

[000154] Isolado como um sólido esbranquiçado (3,0 g, 55%): 1HRMN (300 MHz, CDCI3) δ 7,50 - 7,40 (m, 3H), 7,24 (s, 1H), 7,02 (d, J = 15,9 Hz, 1H), 6,90 (d, J = 9,0 Hz, 2H), 6,81 (d, J = 15,9 Hz, 1H), 3,83 (s, 3H), 2,42 (s, 3H); ESIMS m/z 293 ([M+H]+).Exemplo 8: Preparação de (E)-1,2,4-tricloro-5-(4-metoxiestiril)benzeno (C63)

Figure img0082
[000154] Isolated as an off-white solid (3.0 g, 55%): 1 HRMN (300 MHz, CDCl 3 ) δ 7.50 - 7.40 (m, 3H), 7.24 (s, 1H), 7. 02 (d, J = 15.9 Hz, 1H), 6.90 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 15.9 Hz, 1H), 3.83 ( s, 3H), 2.42 (s, 3H); ESIMS m/z 293 ([M+H]+).Example 8: Preparation of (E)-1,2,4-trichloro-5-(4-methoxystyryl)benzene (C63)
Figure img0082

[000155] Em um tubo vedado foram adicionados 1-bromo-2,4,5- triclorobenzeno (3,0 g, 12 mmol), 1,2-dimetoxietano:água (10:1, 30 mL), (E)-2-(4-metoxiestiril)-4,4,5,5-tetrametil-1,3,2-dioxaborolano (C64) (3,7 g, 14 mmol) e carbonato de potássio (3,2 g, 24 mmol). A mistura de reação foi desgaseificada por 10 minutos com argônio, seguido pela adição de tetraquis(trifenilfosfina)paládio(0) (0,55 g, 0,48 mmol). A mistura de reação foi desgaseificada por 10 minutos e então aquecida a 90°C por 16 horas. A mistura de reação foi vertida em água e extraída com acetato de etila. As camadas orgânicas combinadas foram secas sobre sulfato de sódio, filtradas e concentradas. A purificação por cromatografia flash em coluna proveu o composto do título como um sólido esbranquiçado (3,0 g, 80%): 1H RMN (400 MHz, CDCl3) δ 7,73 (s, 1H), 7,50 - 7,45 (m, 3H), 7,20 (d, J = 16,0 Hz, 1H), 7,02 (d, J = 16 Hz, 1H), 6,92 (d, J = 8,0 Hz, 2H), 3,84 (m, 3H); ESIMS m/z 313 ([M+H]+).Exemplo 9: Preparação de (E)-2-(4-metoxiestiril)-4,4,5,5-tetrametil- 1,3,2-dioxaborolano (C64)

Figure img0083
[000155] In a sealed tube were added 1-bromo-2,4,5-trichlorobenzene (3.0 g, 12 mmol), 1,2-dimethoxyethane:water (10:1, 30 mL), (E)- 2-(4-methoxystyril)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (C64) (3.7 g, 14 mmol) and potassium carbonate (3.2 g, 24 mmol) . The reaction mixture was degassed for 10 minutes with argon, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.55 g, 0.48 mmol). The reaction mixture was degassed for 10 minutes and then heated to 90°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by flash column chromatography provided the title compound as an off-white solid (3.0 g, 80%): 1H NMR (400 MHz, CDCl 3 ) δ 7.73 (s, 1H), 7.50 - 7. 45 (m, 3H), 7.20 (d, J = 16.0 Hz, 1H), 7.02 (d, J = 16 Hz, 1H), 6.92 (d, J = 8.0 Hz, 2H), 3.84 (m, 3H); ESIMS m/z 313 ([M+H]+). Example 9: Preparation of (E)-2-(4-methoxystyryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (C64 )
Figure img0083

[000156] Em um balão de fundo redondo de 50 mL foram adiciona- dos 1-etinil-4-metoxibenzeno (4,0 g, 30 mmol), 4,4,5,5-tetrametil-1,3,2- dioxaborolano (3,3 g, 36 mmol), cloridrato de zirconoceno (1,2 g, 4,0 mmol) e trietilamina (2,8 mL, 15 mmol) a 0°C. A mistura de reação foi então agitada a 65°C por 16 horas. A mistura de reação foi vertida em água e extraída com acetato de etila. As camadas orgânicas combinadas foram secas sobre sulfato de sódio, filtradas e concentradas. A purificação por cromatografia flash em coluna proveu o composto do título como um semissólido esbranquiçado (3,0 g, 38%): 1H RMN (400 MHz, CDCl3) δ 7,43 (d, J = 8,8 Hz, 2H), 7,35 (d, J = 18,0 Hz, 1H), 6,86 (d, J = 8,8 Hz, 2H), 6,01 (d, J = 18,0 Hz, 1H), 3,81 (s, 3H), 1,30 (s, 12H).Exemplo 10: Preparação de 3,4,5-triclorobenzaldeído (C65)

Figure img0084
[000156] In a 50 mL round bottom flask were added 1-ethynyl-4-methoxybenzene (4.0 g, 30 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.3 g, 36 mmol), zirconocene hydrochloride (1.2 g, 4.0 mmol) and triethylamine (2.8 mL, 15 mmol) at 0°C. The reaction mixture was then stirred at 65°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by flash column chromatography provided the title compound as an off-white semi-solid (3.0 g, 38%): 1H NMR (400 MHz, CDCl 3 ) δ 7.43 (d, J = 8.8 Hz, 2H) , 7.35 (d, J = 18.0 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 6.01 (d, J = 18.0 Hz, 1H), 3 .81 (s, 3H), 1.30 (s, 12H). Example 10: Preparation of 3,4,5-trichlorobenzaldehyde (C65)
Figure img0084

[000157] Em balão de fundo redondo de 500 mL seco em estufa e ambientado com nitrogênio equipado com um funil de adição de equa- lização de pressão, 5-bromo-1,2,3-triclorobenzeno (10,0 g, 38,4 mmol) foi dissolvido em tetra-hidrofurano (100 mL) e a solução resultante foi resfriada em um banho-maria gelado sob nitrogênio. Cloreto de iso- propil magnésio (2 M de solução de tetra-hidrofurano, 21,1 mL, 42,3 mmol) foi adicionado gota a gota com boa agitação por 15 minutos via funil de adição. Após 0,5 hora, N,N-dimetilformamida (3,72 mL, 48,0 mmol) foi adicionada à solução escura com agitação. Após 0,5 hora adicional, ácido clorídrico (1 N, 100 mL) foi adicionado sob agitação. As camadas foram separadas e a camada orgânica foi lavada com solução salina. As camadas aquosas combinadas foram extraídas com éter e as substâncias orgânicas combinadas foram secas sobre sulfato de sódio, filtradas e concentradas para resultar no composto do título como um sólido branco (mistura 10:1 do composto do título a 1,2,3- triclorobenzeno, 7,96 g, 99%): 1H RMN (CDCl3) δ 9,91 (s, 1H), 7,88 (s, 2H); EIMS m/z 209 ([M]+).Exemplo 11: Preparação de 1-bromo-4-(perfluoroetil)benzeno (C66)

Figure img0085
[000157] In a 500 mL round bottom flask dried in an oven and ambient with nitrogen equipped with a pressure equalizing addition funnel, 5-bromo-1,2,3-trichlorobenzene (10.0 g, 38, 4 mmol) was dissolved in tetrahydrofuran (100 ml) and the resulting solution was cooled in an ice-cold water bath under nitrogen. Iso-propyl magnesium chloride (2M tetrahydrofuran solution, 21.1 mL, 42.3 mmol) was added dropwise with good stirring over 15 minutes via addition funnel. After 0.5 hour, N,N-dimethylformamide (3.72 mL, 48.0 mmol) was added to the dark solution with stirring. After an additional 0.5 hour, hydrochloric acid (1N, 100 ml) was added with stirring. The layers were separated and the organic layer was washed with brine. The combined aqueous layers were extracted with ether and the combined organics were dried over sodium sulfate, filtered and concentrated to give the title compound as a white solid (10:1 mixture of the title compound to 1,2,3-trichlorobenzene , 7.96 g, 99%): 1H NMR (CDCl 3 ) δ 9.91 (s, 1H), 7.88 (s, 2H); EIMS m/z 209 ([M]+).Example 11: Preparation of 1-bromo-4-(perfluoroethyl)benzene (C66)
Figure img0085

[000158] A uma solução agitada de 1-(4-bromofenil)-2,2,2-trifluoroe- tanona (5,00 g, 19,7 mmol) em diclorometano sob argônio foram adici-onados trifluoreto de 4-terc-butil-2,6-dimetilfenilenxofre (2,90 g, 11,8 mmol) e complexo piridínico de fluoreto de hidrogênio (0,190 g, 9,80 mmol) a 0°C. Permitiu-se que a mistura de reação fosse aquecida à temperatura ambiente e agitada por 16 horas. A mistura de reação foi vertida em água e extraída com acetato de etila. Os extratos orgânicos combinados foram secos sobre sulfato de sódio, filtrados e concentrados. A purificação por cromatografia flash em coluna forneceu o composto do título como um líquido incolor (1,00 g, 20%): 1H RMN (300 MHz, CDCl3) δ 7,65 (d, J = 9,0 Hz, 2H), 7,47 (d, J = 9,0 Hz, 2H); EIMS m/z 274 ([M]+).Exemplo 12: Preparação de ácido trans-2-cloro-5-(2,2-dicloro-3-(3,5- diclorofenil)ciclopropanocarboxamido)benzoico (C67)

Figure img0086
[000158] To a stirred solution of 1-(4-bromophenyl)-2,2,2-trifluoroethanone (5.00 g, 19.7 mmol) in dichloromethane under argon was added 4-tert-trifluoride. butyl-2,6-dimethylphenylsulfur (2.90 g, 11.8 mmol) and hydrogen fluoride pyridine complex (0.190 g, 9.80 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by flash column chromatography provided the title compound as a colorless liquid (1.00 g, 20%): 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 9.0 Hz, 2H) , 7.47 (d, J = 9.0 Hz, 2H); EIMS m/z 274 ([M]+).Example 12: Preparation of trans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido)benzoic acid (C67)
Figure img0086

[000159] A uma solução de ácido trans-2,2-dicloro-3-(3,5-diclorofenil) ciclopropanocarboxílico (C1) (0,300 g, 1,00 mmol) em diclorometano (5,00 mL) agitada a 0°C foi adicionado N,N-dimetilformamida (1 gota) seguida por cloreto de oxalila (0,131 mL, 1,50 mmol) ao longo de 2 mi-nutos. O banho-maria gelado foi removido e se permitiu que a reação aquecesse até a temperatura ambiente ao longo de 90 minutos. A reação foi então concentrada para produzir um semissólido amarelo- alaranjado. O semissólido foi dissolvido em diclorometano (3,5 mL) e a solução foi adicionada lentamente a uma solução resfriada de ácido5- amino-2-clorobenzoico (0,206 g, 1,20 mmol) e trietilamina (0,209 mL, 1,50 mmol) em diclorometano (7 mL). O banho-maria gelado foi removido e se permitiu que a reação aquecesse até a temperatura ambiente ao longo de 90 minutos. A reação foi diluída com diclorometano (10 mL) e lavada com ácido clorídrico (0,1 N). A lama resultante foi filtrada e o sólido, lavado com água. O sólido precipitado foi seco em uma estufa a vácuo a 40°C para prover o composto do título como um sólido marrom claro (0,421 g, 93%): pf 234 - 236°C; 1H RMN (400 MHz, DMSO-d6) δ 13,47 (s, 1H), 10,90 (s, 1H), 8,16 (d, J = 2,3 Hz, 1H), 7,78 (dd, J = 8,7, 2,4 Hz, 1H), 7,59 (m, 4H), 3,56 (dd, J = 49,8, 8,5 Hz, 2H), 1,09 (m, 1H); 13C RMN (101 MHz, DMSO-d6) δ 166,26, 165,77, 162,61, 137,57, 137,27, 134,04, 132,18, 131,44, 131,22, 127,88, 127,66, 126,40, 125,92, 122,88, 121,17, 102,37, 62,11, 38,41, 36,83; ESIMS m/z 454 ([M+H]+).Exemplo 13: Preparação de trans-2-Cloro-N-(ciclopropil-5-(2,2-dicloro- 3-(3,5-diclorofenil)ciclopropanocarboxamido)benzamida (F1)

Figure img0087
[000159] To a solution of trans-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxylic acid (C1) (0.300 g, 1.00 mmol) in dichloromethane (5.00 mL) stirred at 0° C was added N,N-dimethylformamide (1 drop) followed by oxalyl chloride (0.131 ml, 1.50 mmol) over 2 minutes. The ice-cold water bath was removed and the reaction was allowed to warm to room temperature over 90 minutes. The reaction was then concentrated to produce a yellow-orange semi-solid. The semi-solid was dissolved in dichloromethane (3.5 mL) and the solution was added slowly to a cooled solution of 5-amino-2-chlorobenzoic acid (0.206 g, 1.20 mmol) and triethylamine (0.209 mL, 1.50 mmol) in dichloromethane (7ml). The ice-cold water bath was removed and the reaction was allowed to warm to room temperature over 90 minutes. The reaction was diluted with dichloromethane (10ml) and washed with hydrochloric acid (0.1N). The resulting slurry was filtered and the solid washed with water. The precipitated solid was dried in a vacuum oven at 40°C to provide the title compound as a light brown solid (0.421 g, 93%): mp 234 - 236°C; 1H NMR (400 MHz, DMSO-d6) δ 13.47 (s, 1H), 10.90 (s, 1H), 8.16 (d, J = 2.3 Hz, 1H), 7.78 (dd , J = 8.7, 2.4 Hz, 1H), 7.59 (m, 4H), 3.56 (dd, J = 49.8, 8.5 Hz, 2H), 1.09 (m, 1H); 13C NMR (101 MHz, DMSO-d6) δ 166.26, 165.77, 162.61, 137.57, 137.27, 134.04, 132.18, 131.44, 131.22, 127.88 , 127.66, 126.40, 125.92, 122.88, 121.17, 102.37, 62.11, 38.41, 36.83; ESIMS m/z 454 ([M+H]+).Example 13: Preparation of trans-2-Chloro-N-(cyclopropyl-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido) benzamide (F1)
Figure img0087

[000160] 5-Amino-N-ciclopropil-2-(trifluorometil)benzamida (C69) (0,129 g, 0,528 mmol) e 4-dimetilaminopiridina (0,0700 g, 0,572 mmol) foram adicionados sequencialmente a uma mistura agitada de ácido trans-2,2-dicloro-3-(3,5-diclorofenil)ciclopropanocarboxílico (C1) (0,132 g, 0,440 mmol) e 1-etil-3-(3-dimetilaminopropil)carbodi- imida (0,127 g, 0,660 mmol) em 1,2-dicloroetano (4,40 mL) à temperatura ambiente. A reação foi agitada à temperatura ambiente por 20 horas. Diclorometano foi adicionado e a mistura foi lavada com bicarbonato de sódio aquoso saturado e ácido clorídrico (1 N). A fase orgânica foi seca sobre sulfato de magnésio, filtrada e concentrada para render o composto do título como um sólido amarelo (0,0870 g, 36%).[000160] 5-Amino-N-cyclopropyl-2-(trifluoromethyl)benzamide (C69) (0.129 g, 0.528 mmol) and 4-dimethylaminopyridine (0.0700 g, 0.572 mmol) were sequentially added to a stirred mixture of trans acid -2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxylic (C1) (0.132 g, 0.440 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.127 g, 0.660 mmol) in 1,2-dichloroethane (4.40 ml) at room temperature. The reaction was stirred at room temperature for 20 hours. Dichloromethane was added and the mixture was washed with saturated aqueous sodium bicarbonate and hydrochloric acid (1N). The organic phase was dried over magnesium sulfate, filtered and concentrated to yield the title compound as a yellow solid (0.0870 g, 36%).

[000161] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 13: trans-N-Ciclopropil-5-(2,2-dicloro-3-(3,5-triclorofenil)ciclopropanocarboxamido)-2-(trifluorometil)benzamida (F2)

Figure img0088
[000161] The following compounds were prepared in a manner similar to the procedure described in Example 13: trans-N-Cyclopropyl-5-(2,2-dichloro-3-(3,5-trichlorophenyl)cyclopropanecarboxamido)-2-( trifluoromethyl)benzamide (F2)
Figure img0088

[000162] Isolado como um sólido branco (0,087 g, 17%).trans-N-Ciclopropil-3-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropanocar-boxamido)benzamida (F3)

Figure img0089
[000162] Isolated as a white solid (0.087 g, 17%). trans-N-Cyclopropyl-3-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido)benzamide (F3)
Figure img0089

[000163] Isolado como um sólido branco (0,200 g, 66%).trans-2-Cloro-N-(1-cianociclopropil)-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropanocarboxamido)benzamida (F4)

Figure img0090
[000163] Isolated as a white solid (0.200 g, 66%). trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido) benzamide (F4)
Figure img0090

[000164] Isolado como um semissólido marrom (0,071 g, 55%).trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropanocarboxa-mido)-N-(3,3-difluorociclobutil)benzamida (F5)

Figure img0091
[000164] Isolated as a brown semi-solid (0.071 g, 55%). trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido)-N-(3, 3-difluorocyclobutyl)benzamide (F5)
Figure img0091

[000165] Isolado como um pó marrom amarelado (0,200 g, 74%).trans-2-Cloro-5-(2,2-dicloro-3-(3,4,5-triclorofenil)ciclopropanocarboxa-mido)-N-(3,3-difluorociclobutil)benzamida (F6)

Figure img0092
[000165] Isolated as a yellowish brown powder (0.200 g, 74%). trans-2-Chloro-5-(2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropanecarboxamido)-N- (3,3-difluorocyclobutyl)benzamide (F6)
Figure img0092

[000166] Isolado como um pó esbranquiçado (0,092 g, 67%).trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropanocarboxamido)-N-(tetra-hidrotiofen-3-il)benza- mida (F7)

Figure img0093
[000166] Isolated as an off-white powder (0.092 g, 67%). trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido)-N-(tetrahydrothiophen- 3-yl)benzamide (F7)
Figure img0093

[000167] Isolado como um pó esbranquiçado (0,022 g, 16%):trans-2-Cloro-5-(2,2-dicloro-3-(3,4,5-triclorofenil)ciclopropanocarbo-xamido)-N-(tetra-hidrotiofen-3-il)benzamida (F8)

Figure img0094
[000167] Isolated as an off-white powder (0.022 g, 16%): trans-2-Chloro-5-(2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropanecarboxamid)-N-( tetrahydrothiophen-3-yl)benzamide (F8)
Figure img0094

[000168] Isolado como um pó esbranquiçado (0,040 g, 47%):trans-2-Cloro-5-(2,2-dicloro-3-(3,4-diclorofenil)ciclopropanocarboxa-mido)-N-(3,3-difluorociclobutil)benzamida (F9)

Figure img0095
[000168] Isolated as an off-white powder (0.040 g, 47%): trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropanecarboxamido)-N-(3, 3-difluorocyclobutyl)benzamide (F9)
Figure img0095

[000169] Isolado como um sólido branco (0,084 g, 52%):trans-2-Cloro-N-(1-cianociclopropiletil)-5-(2,2-dicloro-3-(3,4,5-tricloro-fenil)ciclopropanocarboxamido)benzamida (F10)

Figure img0096
[000169] Isolated as a white solid (0.084 g, 52%): trans-2-Chloro-N-(1-cyanocyclopropylethyl)-5-(2,2-dichloro-3-(3,4,5-trichloro-) phenyl)cyclopropanecarboxamido)benzamide (F10)
Figure img0096

[000170] Isolado como um semissólido marrom (0,140 g, 74%): trans-2-Cloro-N-(1-cianociclopropil)-5-(2,2-dicloro-3-(3,4-diclorofenil)ciclopropanocarboxamido)benzamida (F11)

Figure img0097
[000170] Isolated as a brown semi-solid (0.140 g, 74%): trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropanecarboxamido) benzamide (F11)
Figure img0097

[000171] Isolado como um semissólido marrom (0,110 g, 85%):trans-2-Cloro-N-(1-cianociclobutil)-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclo-propanocarboxamido)benzamida (F12)

Figure img0098
[000171] Isolated as a brown semi-solid (0.110 g, 85%): trans-2-Chloro-N-(1-cyanocyclobutyl)-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclo- propanecarboxamido)benzamide (F12)
Figure img0098

[000172] Isolado como uma espuma marrom amarelada (0,060 g, 45%): trans-2-Cloro-N-(1-cianociclobutil)-5-(2,2-dicloro-3-(3,4,5-triclorofenil)ciclopropanocarboxamido)benzamida (F13)

Figure img0099
[000172] Isolated as a yellowish brown foam (0.060 g, 45%): trans-2-Chloro-N-(1-cyanocyclobutyl)-5-(2,2-dichloro-3-(3,4,5-trichlorophenyl) )cyclopropanecarboxamido)benzamide (F13)
Figure img0099

[000173] Isolado como uma espuma marrom amarelada (0,077 g, 61%):trans-2-Cloro-N-(1-cianociclobutil)-5-(2,2-dicloro-3-(3,4-diclorofenil)ci-clopropanocarboxamido)benzamida (F14)

Figure img0100
[000173] Isolated as a yellowish brown foam (0.077 g, 61%): trans-2-Chloro-N-(1-cyanocyclobutyl)-5-(2,2-dichloro-3-(3,4-dichlorophenyl)ci -chloropropanecarboxamido)benzamide (F14)
Figure img0100

[000174] Isolado como uma espuma marrom amarelada (0,072 g, 54%):trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropanocarboxamido)-N-(tietan-3-il)benzamida (F15)

Figure img0101
[000174] Isolated as a yellowish brown foam (0.072 g, 54%): trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido)-N-(tietan-3 -yl)benzamide (F15)
Figure img0101

[000175] Isolado como um pó branco (0,081 g, 62%):trans-2-Cloro-5-(2,2-dicloro-3-(3,4-diclorofenil)ciclopropanocarboxamido)-N-(tietan-3-il)benzamida (F16)

Figure img0102
[000175] Isolated as a white powder (0.081 g, 62%): trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropanecarboxamido)-N-(tietan-3- il)benzamide (F16)
Figure img0102

[000176] Isolado como um semissólido amarelo claro (0,089 g, 68%): trans-2-Cloro-5-(2,2-dicloro-3-(3,4,5-triclorofenil)ciclopropanocarbo-xamido)-N-(tietan-3-il)benzamida (F17)

Figure img0103
[000176] Isolated as a light yellow semi-solid (0.089 g, 68%): trans-2-Chloro-5-(2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropanecarboxamid)-N- (thietan-3-yl)benzamide (F17)
Figure img0103

[000177] Isolado como um pó branco (0,082 g, 61%):trans-2-Cloro-N-(1-cianociclopropil)-5-(2,2-dicloro-3-(3-(trifluorometil)fenil)ciclopropanocarboxamido)benzamida (F18)

Figure img0104
[000177] Isolated as a white powder (0.082 g, 61%): trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-(3-(trifluoromethyl)phenyl)cyclopropanecarboxamido )benzamide (F18)
Figure img0104

[000178] Isolado como um sólido branco (0,088 g, 61%):trans-2-Cloro-5-(2,2-dicloro-3-(3-(trifluorometil)fenil)ciclopropanocar-boxamido)-N-(3,3-difluorociclobutil)benzamida (F19)

Figure img0105
[000178] Isolated as a white solid (0.088 g, 61%): trans-2-Chloro-5-(2,2-dichloro-3-(3-(trifluoromethyl)phenyl)cyclopropanecarboxamido)-N-(3 ,3-difluorocyclobutyl)benzamide (F19)
Figure img0105

[000179] Isolado como um sólido branco (0,110 g, 72%):trans-2-Cloro-5-(2,2-dicloro-3-(2,4,5-triclorofenil)ciclopropanocarbo-xamido)-N-(3,3-difluorociclobutil)benzamida (F20)

Figure img0106
[000179] Isolated as a white solid (0.110 g, 72%): trans-2-Chloro-5-(2,2-dichloro-3-(2,4,5-trichlorophenyl)cyclopropanecarboxamid)-N-( 3,3-difluorocyclobutyl)benzamide (F20)
Figure img0106

[000180] Isolado como um sólido branco (0,058 g, 40%):trans-2-Cloro-5-(2,2-dicloro-3-(3-cloro-4-(trifluorometóxi)fenil) ciclopro- panocarboxamido)-N-(3,3-difluorociclobutil)benzamida (F21)

Figure img0107
[000180] Isolated as a white solid (0.058 g, 40%): trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-(trifluoromethoxy)phenyl)cyclopropanecarboxamido)- N-(3,3-difluorocyclobutyl)benzamide (F21)
Figure img0107

[000181] Isolado como um sólido branco (0,092 g, 65%):trans-2-Cloro-5-(2,2-dicloro-3-(4-(trifluorometil)fenil) ciclopropanocar-boxamido)-N-(3,3-difluorociclobutil)benzamida (F22)

Figure img0108
[000181] Isolated as a white solid (0.092 g, 65%): trans-2-Chloro-5-(2,2-dichloro-3-(4-(trifluoromethyl)phenyl)cyclopropanecarboxamido)-N-(3 ,3-difluorocyclobutyl)benzamide (F22)
Figure img0108

[000182] Isolado como um sólido branco (0,108 g, 71%):trans-2-Cloro-N-(1-cianociclopropil)-5-(2,2-dicloro-3-(4-trifluorometil)fenil)ciclopropanocarboxamido)benzamida (F23)

Figure img0109
[000182] Isolated as a white solid (0.108 g, 71%): trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-(4-trifluoromethyl)phenyl)cyclopropanecarboxamido) benzamide (F23)
Figure img0109

[000183] Isolado como um sólido branco (0,022 g, 15%):trans -5-(3-(3,5-Bis(trifluorometil)fenil)-2,2-diclorociclopropanocarbo-xamido)-2-cloro-N-(3,3-difluorociclobutil)benzamida (F24)

Figure img0110
[000183] Isolated as a white solid (0.022 g, 15%): trans -5-(3-(3,5-Bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropanecarboxamid)-2-chloro-N- (3,3-difluorocyclobutyl)benzamide (F24)
Figure img0110

[000184] Isolado como um sólido branco (0,052 g, 37%):trans-5-(3-(3,5-Bis(trifluorometil)fenil)-2,2-diclorociclopropanocarbo- xamido)-2-cloro-N-( 1 -cianociclopropil)benzamida (F25)

Figure img0111
[000184] Isolated as a white solid (0.052 g, 37%): trans-5-(3-(3,5-Bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropanecarboxamido)-2-chloro-N- (1 -cyanocyclopropyl)benzamide (F25)
Figure img0111

[000185] Isolado como um sólido branco (0,024 g, 18%):trans-2-Cloro-5-(2,2-dicloro-3-(3-cloro-5-(trifluorometil)fenil) ciclopropa-nocarboxamido)-N-(3,3-difluorociclobutil)benzamida (F26)

Figure img0112
[000185] Isolated as a white solid (0.024 g, 18%): trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-5-(trifluoromethyl)phenyl)cyclopropanecarboxamido)- N-(3,3-difluorocyclobutyl)benzamide (F26)
Figure img0112

[000186] Isolado como um sólido branco (0,052 g, 36%):trans-2-Cloro-N-(1-cianociclopropil)-5-(2,2-dicloro-3-(3-cloro-5-(triflu-orometil)fenil)ciclopropanocarboxamido)benzamida (F27)

Figure img0113
[000186] Isolated as a white solid (0.052 g, 36%): trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-(3-chloro-5-(triflu) -oromethyl)phenyl)cyclopropanecarboxamido)benzamide (F27)
Figure img0113

[000187] Isolado como um sólido branco (0,022 g, 15%):trans-2-Cloro-5-(2,2-dicloro-3-(3,5-dibromofenil) ciclopropanocarboxa-mido)-N-(3,3-difluorociclobutil)benzamida (F28)

Figure img0114
[000187] Isolated as a white solid (0.022 g, 15%): trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dibromophenyl)cyclopropanecarboxamido)-N-(3, 3-difluorocyclobutyl)benzamide (F28)
Figure img0114

[000188] Isolado como um sólido branco (0,039 g, 29%):trans-2-Cloro-N-(1-cianopropil)-5-(2,2-dicloro-3-(3,5-dibromofenil)ciclo- propanocarboxamido)benzamida (F29)

Figure img0115
[000188] Isolated as a white solid (0.039 g, 29%): trans-2-Chloro-N-(1-cyanopropyl)-5-(2,2-dichloro-3-(3,5-dibromophenyl)cyclo- propanecarboxamido)benzamide (F29)
Figure img0115

[000189] Isolado como uma película transparente (0,013 g, 10%)trans-2-Cloro-5-(2,2-dicloro-3-(3,5-dicloro-4-fluorofenil)ciclopropanocar- boxamido)-N-(3,3-difluorociclobutil)benzamida (F30)

Figure img0116
[000189] Isolated as a clear film (0.013 g, 10%) trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichloro-4-fluorophenyl)cyclopropanecarboxamido)-N- (3,3-difluorocyclobutyl)benzamide (F30)
Figure img0116

[000190] Isolado como um sólido branco (0,037 g, 25%):trans-2-Cloro-N-(1-cianociclopropil)-5-(2,2-dicloro-3-(3,5-diclorofenil)-4- fluorofenil)ciclopropanocarboxamido)benzamida (F31)

Figure img0117
[000190] Isolated as a white solid (0.037 g, 25%): trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-(3,5-dichlorophenyl)-4 - fluorophenyl)cyclopropanecarboxamido)benzamide (F31)
Figure img0117

[000191] Isolado como uma película transparente (0,015 g, 10%):trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil) ciclopropanocarboxami-do)-N-((3,3-difluorociclobutil)-N-metilbenzamida (F32)

Figure img0118
[000191] Isolated as a clear film (0.015 g, 10%): trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl) cyclopropanecarboxamido)-N-((3 ,3-difluorocyclobutyl)-N-methylbenzamide (F32)
Figure img0118

[000192] Isolado como uma espuma branca (0,118 g, 85%):trans-2-Cloro-5-(2,2-dicloro-3-(3,4-diclorofenil)ciclopropanocarbo- xamido)-N-(3,3-difluorociclobutil)-N-metilbenzamida (F33)

Figure img0119
[000192] Isolated as a white foam (0.118 g, 85%): trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropanecarboxamido)-N-(3, 3-difluorocyclobutyl)-N-methylbenzamide (F33)
Figure img0119

[000193] Isolado como uma espuma branca (0,116 g, 83%):trans-2-Cloro-5-(2,2-dicloro-3-(3,4,5-triclorofenil)ciclopropanocar-boxamido)-N-(3,3-difluorociclobutil)-N-metilbenzamida (F34)

Figure img0120
[000193] Isolated as a white foam (0.116 g, 83%): trans-2-Chloro-5-(2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropanecarboxamido)-N-( 3,3-difluorocyclobutyl)-N-methylbenzamide (F34)
Figure img0120

[000194] Isolado como uma espuma branca (0,071 g, 54%):trans-2-Cloro-N-(3-cianociclopentil)-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropanocarboxamido)benzamida (F35)

Figure img0121
[000194] Isolated as a white foam (0.071 g, 54%): trans-2-Chloro-N-(3-cyanocyclopentyl)-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido) benzamide (F35)
Figure img0121

[000195] Isolado como uma espuma branca (0,136 g, 88%):trans-2-Cloro-N-(3-cianociclopentil)-5-(2,2-dicloro-3-(3,4-diclorofenil)ciclopropanocarboxamido)benzamida (F36)

Figure img0122
[000195] Isolated as a white foam (0.136 g, 88%): trans-2-Chloro-N-(3-cyanocyclopentyl)-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropanecarboxamido) benzamide (F36)
Figure img0122

[000196] Isolado como um pó esbranquiçado (0,114 g, 74%):trans-2-Cloro-5-(2,2-dicloro-3-fenilciclopropanocarboxamido)-N-(3,3- difluorociclobutil)benzamida (F37)

Figure img0123
[000196] Isolated as an off-white powder (0.114 g, 74%): trans-2-Chloro-5-(2,2-dichloro-3-phenylcyclopropanecarboxamido)-N-(3,3-difluorocyclobutyl)benzamide (F37)
Figure img0123

[000197] Isolado como um sólido branco (0,024 g, 14%): trans-2-Cloro-N-(1-cianociclopropil)-5-(2,2-dicloro-3-fenilciclopropano- carboxamido)benzamida (F38)

Figure img0124
[000197] Isolated as a white solid (0.024 g, 14%): trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-phenylcyclopropane-carboxamido)benzamide (F38)
Figure img0124

[000198] Isolado como uma película amarela (0,008 g, 5%):trans-2-Cloro-N-(3-cianociclopentil)-5-(2,2-dicloro-3-(3,4,5-triclorofenil)ciclopropanocarboxamido)benzamida (F39)

Figure img0125
[000198] Isolated as a yellow film (0.008 g, 5%): trans-2-Chloro-N-(3-cyanocyclopentyl)-5-(2,2-dichloro-3-(3,4,5-trichlorophenyl) cyclopropanecarboxamido)benzamide (F39)
Figure img0125

[000199] Isolado como um pó branco (0,122 g, 78%):trans-2-Cloro-N-ciclobutil-5-(2,2-dicloro-3-(3,5-diclorofenil) ciclopropa-nocarboxamido)benzamida (F40)

Figure img0126
[000199] Isolated as a white powder (0.122 g, 78%): trans-2-Chloro-N-cyclobutyl-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido)benzamide ( F40)
Figure img0126

[000200] Isolado como um pó esbranquiçado (0,137 g, 78%):trans-2-Cloro-N-ciclobutil-5-(2,2-dicloro-3-(3,4-diclorofenil)ciclopropa- nocarboxamido)benzamida (F41)

Figure img0127
[000200] Isolated as an off-white powder (0.137 g, 78%): trans-2-Chloro-N-cyclobutyl-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropanecarboxamido)benzamide ( F41)
Figure img0127

[000201] Isolado como um pó esbranquiçado (0,113 g, 75%):trans-2-Cloro-N-ciclobutil-5-(2,2-dicloro-3-(3,4,5-triclorofenil) ciclopro-panocarboxamido)benzamida (F42)

Figure img0128
[000201] Isolated as an off-white powder (0.113 g, 75%): trans-2-Chloro-N-cyclobutyl-5-(2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropanecarboxamido) benzamide (F42)
Figure img0128

[000202] Isolado como um pó esbranquiçado (0,121 g, 75%):trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil) ciclopropanocarboxami-do)-N-(4,4-difluorociclo-hexil)benzamida (F43)

Figure img0129
[000202] Isolated as an off-white powder (0.121 g, 75%): trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl) cyclopropanecarboxamido)-N-(4, 4-difluorocyclohexyl)benzamide (F43)
Figure img0129

[000203] Isolado como uma espuma esbranquiçada (0,108 g, 57%): trans-2-Cloro-5-(2,2-dicloro-3-(3,4-diclorofenil) ciclopropanocarboxami-do)-N-(4,4-difluoociclo-hexil)benzamida (F44)

Figure img0130
[000203] Isolated as an off-white foam (0.108 g, 57%): trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropanecarboxamido)-N-(4, 4-difluoocyclohexyl)benzamide (F44)
Figure img0130

[000204] Isolado como um semissólido marrom (0,108 g, 65%): trans-2-Cloro-5-(2,2-dicloro-3-(3,4,5-triclorofenil) ciclopropanocarbo- xamido-N-(4,4-difluorociclo-hexil)benzamida (F45)

Figure img0131
[000204] Isolated as a brown semi-solid (0.108 g, 65%): trans-2-Chloro-5-(2,2-dichloro-3-(3,4,5-trichlorophenyl) cyclopropanecarboxamido-N-(4 ,4-difluorocyclohexyl)benzamide (F45)
Figure img0131

[000205] Isolado como um pó branco (0,089 g, 49%):trans-2-Cloro-5-(2,2-dicloro-3-(3-cloro-5-metilfenil) ciclopropanocarbo-xamido)-N-(3,3-difluorociclobutil)benzamida (F46)

Figure img0132
[000205] Isolated as a white powder (0.089 g, 49%): trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-5-methylphenyl) cyclopropanecarboxamid)-N-( 3,3-difluorocyclobutyl)benzamide (F46)
Figure img0132

[000206] Isolado como uma espuma branca (0,093 g, 66%):trans-2-Cloro-N-(1-(cianociclopropil)-5-(2,2-dicloro-3-(3-cloro-5-metilfenil)ciclopropanocarboxamido)benzamida (F47)

Figure img0133
[000206] Isolated as a white foam (0.093 g, 66%): trans-2-Chloro-N-(1-(cyanocyclopropyl)-5-(2,2-dichloro-3-(3-chloro-5-methylphenyl) )cyclopropanecarboxamido)benzamide (F47)
Figure img0133

[000207] Isolado como um vidro incolor (0,031 g, 23%):trans-2-Cloro-5-(2,2-dicloro-3-(3,5-dicloro-4-metilfenil) ciclopropano-carboxamido)-N-(3,3-difluorociclobutil)benzamida (F48)

Figure img0134
[000207] Isolated as a colorless glass (0.031 g, 23%): trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichloro-4-methylphenyl)cyclopropane-carboxamido)-N -(3,3-difluorocyclobutyl)benzamide (F48)
Figure img0134

[000208] Isolado como um sólido branco (0,094 g, 71%):trans-2-Cloro-N-(1-cianociclopropil)-5-(2,2-dicloro-3-(3,5-dicloro-4- metilfenil)ciclopropanocarboxamido)benzamida (F49)

Figure img0135
[000208] Isolated as a white solid (0.094 g, 71%): trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-(3,5-dichloro-4- methylphenyl)cyclopropanecarboxamido)benzamide (F49)
Figure img0135

[000209] Isolado como uma película incolor (0,011 g, 9%):trans-2-Cloro-5-(2,2-dicloro-3-(3,4-dicloro-5-metilfenil)ciclopropanocar-boxamido)-N-(3,3-difluorociclobutil)benzamida (F50)

Figure img0136
[000209] Isolated as a colorless film (0.011 g, 9%): trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichloro-5-methylphenyl)cyclopropanecarboxamido)-N -(3,3-difluorocyclobutyl)benzamide (F50)
Figure img0136

[000210] Isolado como um sólido branco (0,052 g, 39%):trans-2-Cloro-N-(1-cianociclopropil)-5-(2,2-dicloro-3-(3,4-dicloro-5-metilfenil)ciclopropanocarboxamido)benzamida (F51)

Figure img0137
[000210] Isolated as a white solid (0.052 g, 39%): trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-(3,4-dichloro-5-) methylphenyl)cyclopropanecarboxamido)benzamide (F51)
Figure img0137

[000211] Isolado como uma espuma branca (0,087 g, 69%):Exemplo 14: Preparação de ácido trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropanocarboxamido)-N-morfolinobenzamida (F52)

Figure img0138
[000211] Isolated as a white foam (0.087 g, 69%): Example 14: Preparation of trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido)-N acid -morpholinobenzamide (F52)
Figure img0138

[000212] A uma solução de morfolin-4-amina (0,0200 g, 0,198 mmol) em diclorometano (2 mL) foram adicionados sequencialmente 1-etil-3- (3-dimetilaminopropil)carbodiimida (0,0480 g, 0,248 mmol), 4-dimetila- minopiridina (0,0240 g, 0,198 mmol), e ácido 2-cloro-5-(2,2-dicloro-3- (3,5-diclorofenil)ciclopropanocarboxamido)benzoico (C67)(0,0750 g, 0,165 mmol). A reação foi agitada à temperatura ambiente por 16 horas. A purificação por cromatografia flash em coluna usando 0-100% de acetato de etila/hexanos como eluente forneceu o composto de título como um sólido branco (0,0378 g, 43%).[000212] To a solution of morpholin-4-amine (0.0200 g, 0.198 mmol) in dichloromethane (2 mL) was sequentially added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.0480 g, 0.248 mmol) ), 4-dimethylaminopyridine (0.0240 g, 0.198 mmol), and 2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido)benzoic acid (C67)(0, 0750 g, 0.165 mmol). The reaction was stirred at room temperature for 16 hours. Purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent provided the title compound as a white solid (0.0378 g, 43%).

[000213] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 14:trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropanocarboxa- mido)-N-(oxetan-3-il)benzamida (F53)

Figure img0139
[000213] The following compounds were prepared in a manner similar to the procedure described in Example 14: trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido)-N -(oxetan-3-yl)benzamide (F53)
Figure img0139

[000214] Isolado como um pó branco (0,067 g, 60%):trans-terc-Butil 3-(2-cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropa-nocarboxamido)benzamido)azetidina-1-carboxilato (F54)

Figure img0140
[000214] Isolated as a white powder (0.067 g, 60%): trans-tert-Butyl 3-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido) benzamido)azetidine-1-carboxylate (F54)
Figure img0140

[000215] Isolado como um pó verde claro (0,805 g, 60%):Exemplo 15: Preparação de trans-2-cloro-5-(2,2-dicloro-3-(3,5-dicloro- fenil)ciclopropanocarboxamido-N-(tetra-hidro-2H-pirano-4-il)benzamidaÍF55)

Figure img0141
[000215] Isolated as a light green powder (0.805 g, 60%): Example 15: Preparation of trans-2-chloro-5-(2,2-dichloro-3-(3,5-dichloro-phenyl)cyclopropanecarboxamido- N-(tetrahydro-2H-pyran-4-yl)benzamide (F55)
Figure img0141

[000216] A uma solução de ácido 2-cloro-5-(2,2-dicloro-3-(3,5-dicloro- fenil)ciclopropanocarboxamido)benzoico (C67) (0,200 g, 0,441 mmol) em diclorometano (2,2 mL) agitada a 0°C foi adicionada N,N-dime- tilformamida (1 gota) seguida por cloreto de oxalila (0,0579 mL, 0,661 mmol). O banho-maria gelado foi removido e se permitiu que a reação aquecesse até a temperatura ambiente ao longo de 90 minutos. A reação foi então concentrada para obter uma espuma colorida em creme (0,210 g). A metade do cloreto de ácido (0,100 g, 0,212 mL) foi dissolvida em diclorometano (2 mL) e a solução foi adicionada a uma solução resfriada de tetra-hidro-2H-pirano-4-amina (0,0290 g, 0,254 mmol) e trietilamina (0,0440 mL, 0,318 mmol) dissolvida em diclorometano (2 mL). O banho-maria gelado foi removido e a reação foi agitada em temperatura ambiente por 16 horas. A purificação por cromatografia flash em coluna usando 0-40% de acetato de etila/hexanos como eluente forneceu o composto do título como um sólido branco (0,0339 g, 29%).Exemplo 16: Preparação de diastereoisômeros de trans-2-cloro-5-(2,2- dicloro-3-(3,4,5-triclorofenil)ciclopropanocarboxamido)-N-(1-oxidotietan -3-il)benzamida (F56) e (F57)

Figure img0142
[000216] To a solution of 2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido)benzoic acid (C67) (0.200 g, 0.441 mmol) in dichloromethane (2, 2ml) stirred at 0°C was added N,N-dimethylformamide (1 drop) followed by oxalyl chloride (0.0579ml, 0.661mmol). The ice-cold water bath was removed and the reaction was allowed to warm to room temperature over 90 minutes. The reaction was then concentrated to obtain a cream colored foam (0.210 g). Half of the acid chloride (0.100 g, 0.212 mL) was dissolved in dichloromethane (2 mL) and the solution was added to a cooled solution of tetrahydro-2H-pyran-4-amine (0.0290 g, 0.254 mmol ) and triethylamine (0.0440 ml, 0.318 mmol) dissolved in dichloromethane (2 ml). The cold water bath was removed and the reaction was stirred at room temperature for 16 hours. Purification by flash column chromatography using 0-40% ethyl acetate/hexanes as eluent provided the title compound as a white solid (0.0339 g, 29%). Example 16: Preparation of trans-2-diastereoisomers chloro-5-(2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropanecarboxamido)-N-(1-oxidothietan-3-yl)benzamide (F56) and (F57)
Figure img0142

[000217] A uma solução de trans-2-cloro-5-(2,2-dicloro-3-(3,4,5-triclo- rofenil)ciclopropanocarboxamido)-N-(tietan-3-il)benzamida (F17) (0,150 g, 0,268 mmol) em diclorometano (2,68 mL) foi adicionado ácido meta- cloroperoxibenzoico (0,0630 g, 0,282 mmol). A reação foi agitada à temperatura ambiente por 3 horas. Adicionou-se bicarbonato de sódio aquoso saturado e a mistura foi extraída com acetato de etila. As fases orgânicas combinadas foram lavadas com salmoura, secaram sobre sulfato de magnésio, foram filtradas e concentradas. Purificação por cromatografia em coluna flash usando 0-15% de metanol/diclorome- tano como eluente forneceu o composto de título (F56) como um sólido branco (0,0390 g, 24%) e (F57) como um sólido branco (0,0200 g, 12%).Exemplo 17: Preparação de trans-2-cloro-5-(2,2-dicloro-3-(3,4,5-triclo- rofenil)ciclopropanocarboxamido)-N-( 1, 1 -dioxidotietan-3-il)benzamida (F58)

Figure img0143
[000217] To a solution of trans-2-chloro-5-(2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropanecarboxamido)-N-(tietan-3-yl)benzamide (F17 ) (0.150 g, 0.268 mmol) in dichloromethane (2.68 mL) was added meta-chloroperoxybenzoic acid (0.0630 g, 0.282 mmol). The reaction was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash column chromatography using 0-15% methanol/dichloromethane as eluant furnished the title compound (F56) as a white solid (0.0390 g, 24%) and (F57) as a white solid (0 0.0200 g, 12%). Example 17: Preparation of trans-2-chloro-5-(2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropanecarboxamido)-N-(1, 1 -dioxidothietan-3-yl)benzamide (F58)
Figure img0143

[000218] A uma solução de trans-2-cloro-5-(2,2-dicloro-3-(3,4,5-triclo- rofenil)ciclopropanocarboxamido)-N-(tietan-3-il)benzamida (F17) (0,140 g, 0,250 mmol) em diclorometano (2,5 mL) foi adicionado ácido meta- cloroperoxibenzoico (0,140 g, 0,626 mmol). A reação foi agitada à temperatura ambiente por 3 horas. Adicionou-se bicarbonato de sódio aquoso saturado e a mistura foi extraída com acetato de etila. As fases orgânicas combinadas foram lavadas com salmoura, secaram sobre sulfato de magnésio, foram filtradas e concentradas. A purificação por cromatografia de coluna de flash usando 0-15% de metanol/clorome- tano forneceu os compostos do título como um sólido de amarelo claro (0,0460 g, 30%).Exemplo 18: Preparação de trans-N-(azetidin-3-il)-2-cloro-5-(2,2-diclo- ro-3-(3,5-diclorofenil)ciclopropanocarboxamido) benzamida (F59)

Figure img0144
[000218] To a solution of trans-2-chloro-5-(2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropanecarboxamido)-N-(tietan-3-yl)benzamide (F17 ) (0.140 g, 0.250 mmol) in dichloromethane (2.5 mL) was added meta-chloroperoxybenzoic acid (0.140 g, 0.626 mmol). The reaction was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash column chromatography using 0-15% methanol/chloromethane provided the title compounds as a pale yellow solid (0.0460 g, 30%). Example 18: Preparation of trans-N-( azetidin-3-yl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido)benzamide (F59)
Figure img0144

[000219] O ácido trifluoroacético (0,082 mL, 1,1 mmol) foi adicionado a uma mistura agitada de trans-terc-butil 3-(2-cloro-5-(2,2-dicloro-3- (3,5-diclorofenil)ciclopropanocarboxamido)benzamido)azetidina-1-car- boxilato (F54) (0,065 g, 0,11 mmol) em diclorometano (1,4 mL) em 23°C. A solução incolor homogênea resultante foi agitada em 23°C por 3 horas. A mistura de reação foi diluída com solução de bicarbonato de sódio aquoso saturado (50 mL) e extraída com diclorometano (9 x 15 mL). As camadas orgânicas combinadas foram secas sobre sulfato de magnésio, filtradas e concentradas para resultar no produto desejado como um pó branco (0,047 g, 87%).Exemplo 19: Preparação de trans-2-cloro-5-(2,2-dicloro-3-(3,5-dicloro- fenil)ciclopropanocarboxamido)-N-(1-(2,2,2-trifluoroacetil)azetidin-3-il) benzamida (F60)

Figure img0145
[000219] Trifluoroacetic acid (0.082 mL, 1.1 mmol) was added to a stirred mixture of trans-tert-butyl 3-(2-chloro-5-(2,2-dichloro-3-(3,5-) dichlorophenyl)cyclopropanecarboxamido)benzamido)azetidine-1-carboxylic acid (F54) (0.065 g, 0.11 mmol) in dichloromethane (1.4 mL) at 23°C. The resulting homogeneous colorless solution was stirred at 23°C for 3 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (50ml) and extracted with dichloromethane (9x15ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the desired product as a white powder (0.047 g, 87%). Example 19: Preparation of trans-2-chloro-5-(2,2-dichloro -3-(3,5-dichlorophenyl)cyclopropanecarboxamido)-N-(1-(2,2,2-trifluoroacetyl)azetidin-3-yl)benzamide (F60)
Figure img0145

[000220] O ácido trifluoroacético (0,13 mL, 1,7 mmol) foi adicionado a uma mistura agitada de trans-terc-butil 3-(2-cloro-5-(2,2-dicloro-3- (3,5-diclorofenil)ciclopropanocarboxamido)benzamido)azetidina-1-car- boxilato (F54) (0,10 g, 0,17 mmol) em diclorometano (1,6 mL) em 23°C. A solução incolor homogênea resultante foi agitada em 23°C por 4 horas. A mistura de reação foi concentrada e o resíduo foi reconstituído em diclorometano (1,6 mL). Trietilamina (0,034 mL, 0,25 mmol) e ácido 2-metoxiacético (0,020 mL, 0,25 mmol) foram adicionados se- guidos por cloridrato de 1-etil-3-(3-dimetilaminopropil)-carbodiimida (0,063 g, 0,33 mmol), 4-dimetilaminopiridina (0,030 g, 0,25 mmol). A solução amarela brilhante homogênea resultante foi agitada em 23°C por 72 horas. A mistura de reação foi concentrada e o resíduo foi purificado por cromatografia flash em coluna de flash de fase reversa usando 5-100% de acetonitrila/água como eluente para fornecer o produto do título como um pó branco (0,042 g, 42%).Exemplo 20: Preparação de 5-Amino-2-cloro-N-(ciclopropilbenzamida (C68)

Figure img0146
[000220] Trifluoroacetic acid (0.13 ml, 1.7 mmol) was added to a stirred mixture of trans-tert-butyl 3-(2-chloro-5-(2,2-dichloro-3-3, 5-dichlorophenyl)cyclopropanecarboxamido)benzamido)azetidine-1-carboxylic acid (F54) (0.10 g, 0.17 mmol) in dichloromethane (1.6 mL) at 23°C. The resulting homogeneous colorless solution was stirred at 23°C for 4 hours. The reaction mixture was concentrated and the residue was reconstituted in dichloromethane (1.6 ml). Triethylamine (0.034 mL, 0.25 mmol) and 2-methoxyacetic acid (0.020 mL, 0.25 mmol) were added followed by 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.063 g, 0 .33 mmol), 4-dimethylaminopyridine (0.030 g, 0.25 mmol). The resulting homogeneous bright yellow solution was stirred at 23°C for 72 hours. The reaction mixture was concentrated and the residue was purified by reverse phase flash column chromatography using 5-100% acetonitrile/water as eluent to furnish the title product as a white powder (0.042 g, 42%). Example 20: Preparation of 5-Amino-2-chloro-N-(cyclopropylbenzamide (C68)
Figure img0146

[000221] 2-Cloro-N-ciclopropil-5-nitrobenzamida (C79) (0,130 g, 0,540 mmol) foi dissolvido em acetato de etila (2,5 mL). Etanol (2,5 mL) foi adi-cionado para dissolver o material. Ferro (0,181 g, 3,24 mmol) foi adicio-nado seguido de água (0,5 mL) em seguida, ácido acético (0,866 mL, 15,1 mmol) e a mistura agitada em temperatura ambiente por 5 dias. A reação foi filtrada através de Celite®, diluída com água e extraída com acetato de etila. As fases orgânicas combinadas foram secas sobre sulfato de magnésio, filtradas e concentradas para fornecer o composto do título como um sólido amarelo (0,112 g, 88%): 1H RMN (400 MHz, CDCl3) δ 7,10 (d, J = 8,6 Hz, 1H), 6,96 (d, J = 2,9 Hz, 1H), 6,63 (dd, J = 8,6, 2,9 Hz, 1H), 6,44 (s, 1H), 3,78 (s, 2H), 2,95 - 2,82 (m, 1H), 0,89 - 0,82 (m, 2H), 0,66 - 0,60 (m, 2H); EIMS m/z 211 ([M]+).Exemplo 21: Preparação de 5-amino-N-ciclopropil-2-(trifluorometil)ben- zamida (C69)

Figure img0147
[000221] 2-Chloro-N-cyclopropyl-5-nitrobenzamide (C79) (0.130 g, 0.540 mmol) was dissolved in ethyl acetate (2.5 mL). Ethanol (2.5 mL) was added to dissolve the material. Iron (0.181 g, 3.24 mmol) was added followed by water (0.5 mL) then acetic acid (0.866 mL, 15.1 mmol) and the mixture stirred at room temperature for 5 days. The reaction was filtered through Celite®, diluted with water and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to furnish the title compound as a yellow solid (0.112 g, 88%): 1H NMR (400 MHz, CDCl 3 ) δ 7.10 (d, J = 8 0.6 Hz, 1H), 6.96 (d, J = 2.9 Hz, 1H), 6.63 (dd, J = 8.6, 2.9 Hz, 1H), 6.44 (s, 1H ), 3.78 (s, 2H), 2.95 - 2.82 (m, 1H), 0.89 - 0.82 (m, 2H), 0.66 - 0.60 (m, 2H); EIMS m/z 211 ([M]+).Example 21: Preparation of 5-amino-N-cyclopropyl-2-(trifluoromethyl)benzamide (C69)
Figure img0147

[000222] A uma solução de N-ciclopropil-5-nitro-2-(trifluorometil) benzamida (0,189 g, 0,689 mmol) em metanol (2,3 mL) e água (1,1 mL) foram adicionados pó de ferro (0,192 g, 3,45 mmol) e cloreto de amônio (0,111 g, 2,07 mmol). A reação foi aquecida a 60°C por 2 horas. A reação foi filtrada através de Celite®. O filtrado foi diluído com diclorometano e extraído com ácido clorídrico (1 N). As fases aquosas combinadas foram neutralizadas com bicarbonato de sódio aquoso saturado e extraídas com diclorometano. As fases orgânicas combinadas foram secas sobre sulfato de magnésio, filtradas e concentradas para render o composto do título como um sólido amarelo claro (0,136 g, 73%): 1H RMN (400 MHz, CDCl3) δ 7,40 (d, J = 8,5 Hz, 1H), 6,74 (d, J = 2,4 Hz, 1H), 6,70 6,64 (m, 1H), 5,86 (s, 1H), 4,09 (s, 2H), 2,90 2,80 (m, 1H), 0,91 0,82 (m, 2H), 0,66 0,57 (m, 2H); IR (película fina) 3333, 3249, 1627 cm-1; EIMS m/z 244 ([M]+).[000222] To a solution of N-cyclopropyl-5-nitro-2-(trifluoromethyl)benzamide (0.189 g, 0.689 mmol) in methanol (2.3 mL) and water (1.1 mL) were added iron powder ( 0.192 g, 3.45 mmol) and ammonium chloride (0.111 g, 2.07 mmol). The reaction was heated to 60°C for 2 hours. The reaction was filtered through Celite®. The filtrate was diluted with dichloromethane and extracted with hydrochloric acid (1N). The combined aqueous phases were neutralized with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to yield the title compound as a pale yellow solid (0.136 g, 73%): 1H NMR (400 MHz, CDCl 3 ) δ 7.40 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.70 6.64 (m, 1H), 5.86 (s, 1H), 4.09 (s , 2H), 2.90 2.80 (m, 1H), 0.91 0.82 (m, 2H), 0.66 0.57 (m, 2H); IR (thin film) 3333, 3249, 1627 cm-1; EIMS m/z 244 ([M]+).

[000223] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 21: 5-Amino-2-cloro-N-( 1 -cianociclopropil)benzamida (C70)

Figure img0148
[000223] The following compounds were prepared in a manner similar to the procedure described in Example 21: 5-Amino-2-chloro-N-(1-cyanocyclopropyl)benzamide (C70)
Figure img0148

[000224] Isolado como um sólido amarelo (0,326 g, 75%): 1H RMN (400 MHz, DMSO-d6) δ 9,23 (s, 1H), 7,08 (d, J = 8,6 Hz, 1H), 6,64 - 6,53 (m, 2H), 5,44 (s, 2H), 1,55 (dd, J = 8,2, 5,5 Hz, 2H), 1,19 (dd, J = 8,0, 5,4 Hz, 2H); IR (película fina) 3468, 3261, 2245, 1655 cm-1; EIMS m/z 236 ([M]+).Exemplo 22: Preparação de 5-amino-2-cloro-N-(3,3-difluorociclobutil) benzamida (C71)

Figure img0149
[000224] Isolated as a yellow solid (0.326 g, 75%): 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 7.08 (d, J = 8.6 Hz, 1H ), 6.64 - 6.53 (m, 2H), 5.44 (s, 2H), 1.55 (dd, J = 8.2, 5.5 Hz, 2H), 1.19 (dd, J = 8.0, 5.4 Hz, 2H); IR (thin film) 3468, 3261, 2245, 1655 cm-1; EIMS m/z 236 ([M]+).Example 22: Preparation of 5-amino-2-chloro-N-(3,3-difluorocyclobutyl)benzamide (C71)
Figure img0149

[000225] Cloridrato de 1-etil-3-(3-dimetilaminopropil)-carbodiimida (0,840 g, 4,40 mmol) e 4-dimetilaminopiridina (0,460 g, 3,80 mmol) foram adicionados sequencialmente a uma mistura agitada de ácido 5- amino-2-clorobenzoico (0,500 g, 2,90 mmol), cloridrato de 3,3-diflu- orociclobutilamina (0,500 g, 3,50 mmol) e trietilamina (0,490 mL, 3,50 mmol) em diclorometano (15 mL) a 23°C. A mistura cinza heterogênea resultante foi agitada a 23°C por 96 horas. A mistura de reação foi concentrada e o resíduo foi purificado por cromatografia flash em coluna de fase reversa usando 5-100% de acetonitrila/água como eluente. O resíduo foi transformado em pasta fluida em diclorometano e vácuo filtrado para obter o produto desejado como um pó marrom claro (0,530 g, 70%): 1H RMN (400 MHz, DMSO-d6) δ 8,77 (d, J = 7 Hz, 1H), 7,06 (m, 1H), 6,56-6,61 (m, 2H), 5,41 (br s, 2H), 4,17 (m, 1H), 2,893,01 (m, 2H), 2,56-2,70 (m, 2H); IR (película fina) 3482 (w), 3372 (w), 3251 (w), 2917 (m), 2850 (m), 1697 (w), 1631 (s), 1599 (s), 1577 (m), 1540 (s), 1478 (s) cm-1; ESIMS m/z 261 ([M+H]+).Exemplo 23: Preparação de 5-amino-2-cloro-N-(tetra-hidrotiofen-3- il)benzamida (C72)

Figure img0150
[000225] 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.840 g, 4.40 mmol) and 4-dimethylaminopyridine (0.460 g, 3.80 mmol) were sequentially added to a stirred mixture of acid. - amino-2-chlorobenzoic (0.500 g, 2.90 mmol), 3,3-difluorocyclobutylamine hydrochloride (0.500 g, 3.50 mmol) and triethylamine (0.490 mL, 3.50 mmol) in dichloromethane (15 mL) ) at 23°C. The resulting gray heterogeneous mixture was stirred at 23°C for 96 hours. The reaction mixture was concentrated and the residue was purified by reverse phase flash column chromatography using 5-100% acetonitrile/water as eluent. The residue was slurried in dichloromethane and vacuum filtered to obtain the desired product as a light brown powder (0.530 g, 70%): 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 7 Hz, 1H), 7.06 (m, 1H), 6.56-6.61 (m, 2H), 5.41 (br s, 2H), 4.17 (m, 1H), 2.893.01 ( m, 2H), 2.56-2.70 (m, 2H); IR (thin film) 3482 (w), 3372 (w), 3251 (w), 2917 (m), 2850 (m), 1697 (w), 1631 (s), 1599 (s), 1577 (m), 1540 (s), 1478 (s) cm-1; ESIMS m/z 261 ([M+H]+).Example 23: Preparation of 5-amino-2-chloro-N-(tetrahydrothiophen-3-yl)benzamide (C72)
Figure img0150

[000226] Cloridrato de 1-etil-3-(3-dimetilaminopropil)-carbodiimida (1,15 g, 6,00 mmol) e 4-dimetilaminopiridina (0,590 g, 4,80 mmol) foram adicionados sequencialmente a uma mistura agitada de ácido 5- amino-2-clorobenzoico (0,690 g, 4,00 mmol) e tetra-hidrotiofen-3- amina (0,450 g, 4,40 mmol) em diclorometano (16 mL) a 23°C. A solução cinza homogênea resultante foi agitada a 23°C por 16 horas. A mistura de reação foi concentrada e o resíduo foi purificado por croma- tografia em coluna flash de fase reversa usando 5-100% de acetonitri- la/água como eluente para fornecer o composto do título como um óleo marrom claro (0,780 g, 76%): 1H RMN (400 MHz, CDCl3) δ 7,14 (d, J = 9 Hz, 1H), 7,00 (d, J = 3 Hz, 1H), 6,66 (dd, J = 9, 3 Hz, 1H), 6,56 (br s, 1H), 4,91 (m, 1H), 3,78 (br s, 2H), 3,15 (dd, J = 11, 5 Hz, 1H), 2,78-3,02 (m, 3H), 2,29 (m, 1H), 2,08 (m, 1H); IR (película fina) 3340 (w), 3230 (m), 2935 (w), 1634 (s), 1599 (s), 1575 (m), 1520 (s), 1474 (s), 1432 (m) cm-1; ESIMS m/z 257 ([M+H]+).[000226] 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.15 g, 6.00 mmol) and 4-dimethylaminopyridine (0.590 g, 4.80 mmol) were sequentially added to a stirred mixture of 5-amino-2-chlorobenzoic acid (0.690 g, 4.00 mmol) and tetrahydrothiophen-3-amine (0.450 g, 4.40 mmol) in dichloromethane (16 mL) at 23°C. The resulting homogeneous gray solution was stirred at 23°C for 16 hours. The reaction mixture was concentrated and the residue was purified by reverse phase flash column chromatography using 5-100% acetonitrile/water as eluent to furnish the title compound as a light brown oil (0.780 g, 76 %): 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 9 Hz, 1H), 7.00 (d, J = 3 Hz, 1H), 6.66 (dd, J = 9, 3 Hz, 1H), 6.56 (br s, 1H), 4.91 (m, 1H), 3.78 (br s, 2H), 3.15 (dd, J = 11.5 Hz, 1H) , 2.78-3.02 (m, 3H), 2.29 (m, 1H), 2.08 (m, 1H); IR (thin film) 3340 (w), 3230 (m), 2935 (w), 1634 (s), 1599 (s), 1575 (m), 1520 (s), 1474 (s), 1432 (m) cm -1; ESIMS m/z 257 ([M+H]+).

[000227] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 23: 5-Amino-2-cloro-N-( 1 -cianociclobutil)benzamida (C73)

Figure img0151
[000227] The following compounds were prepared in a manner similar to the procedure described in Example 23: 5-Amino-2-chloro-N-(1-cyanocyclobutyl)benzamide (C73)
Figure img0151

[000228] Isolado como um vidro marrom (0,276 g, 27%): 1H RMN (400 MHz, CDCl3) δ 9,33 (br s, 1H), 8,09 (m, 1H), 7,09 (d, J = 9 Hz, 1H), 6,62 (m, 1H), 5,46 (br s, 2H), 2,57-2,71 (m, 2H), 2,33-2,47 (m, 2H), 1,98-2,11 (m, 2H); IR (película fina) 3353 (w), 3222 (w), 2951 (w), 2236 (w), 1647 (s), 1600 (s), 1523 (s), 1476 (s), 1435 (m) cm-1; ESIMS m/z 250 ([M+H]+).5-Amino-2-cloro-N-(tietan-3-il)benzamida (C74)

Figure img0152
[000228] Isolated as a brown glass (0.276 g, 27%): 1H NMR (400 MHz, CDCl 3 ) δ 9.33 (br s, 1H), 8.09 (m, 1H), 7.09 (d, J = 9Hz, 1H), 6.62 (m, 1H), 5.46 (br s, 2H), 2.57-2.71 (m, 2H), 2.33-2.47 (m, 2H), 1.98-2.11 (m, 2H); IR (thin film) 3353 (w), 3222 (w), 2951 (w), 2236 (w), 1647 (s), 1600 (s), 1523 (s), 1476 (s), 1435 (m) cm -1; ESIMS m/z 250 ([M+H]+).5-Amino-2-chloro-N-(tietan-3-yl)benzamide (C74)
Figure img0152

[000229] Isolado como um pó branco (0,680 g, 71%): pf 166-168°C; 1H RMN (400 MHz, DMSO-d6) δ 8,94 (br d, J = 7,5 Hz, 1H), 7,06 (d, J = 8,7 Hz, 1H), 6,52-6,61 (m, 2H), 5,41 (br s, 2H), 5,12 (h, J = 7,5 Hz, 1H), 3,38-3,47 (m, 2H), 3,20-3,27 (m, 2H); IR (película fina) 3424 (w), 3303 (m), 2943 (w), 1639 (s), 1598 (m), 1578 (m), 1523 (s), 1474 (m) cm-1; ESIMS m/z 243 ([M+H]+).5-Amino-2-cloro-N-(ciclobutilbenzamida (C75)

Figure img0153
[000229] Isolated as a white powder (0.680 g, 71%): mp 166-168°C; 1H NMR (400 MHz, DMSO-d6) δ 8.94 (br d, J = 7.5 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 6.52-6, 61 (m, 2H), 5.41 (br s, 2H), 5.12 (h, J = 7.5Hz, 1H), 3.38-3.47 (m, 2H), 3.20- 3.27 (m, 2H); IR (thin film) 3424 (w), 3303 (m), 2943 (w), 1639 (s), 1598 (m), 1578 (m), 1523 (s), 1474 (m) cm-1; ESIMS m/z 243 ([M+H]+).5-Amino-2-chloro-N-(cyclobutylbenzamide (C75)
Figure img0153

[000230] Isolado como um pó esbranquiçado (): pf 130-132°C; 1H RMN (400 MHz, DMSO-d6) δ 8,49 (br d, J = 8 Hz, 1H), 7,04 (d, J = 8,4 Hz, 1H), 6,52-6,59 (m, 2H), 5,36 (br s, 2H), 4,31 (m, 1H), 2,13-2,23 (m, 2H), 1,91-2,02 (m, 2H), 1,58-1,69 (m, 2H); IR (película fina) 3447 (w), 3334 (m), 3283 (m), 2991 (w), 2942 (w), 2861 (w), 1618 (s), 1601 (s), 1541 (s), 1476 (m), 1428 (m) cm-1; ESIMS m/z 225 ([M+H]+).Exemplo 24: Preparação de 5-amino-2-cloro-N-(3,3-difluorociclobutil)- N-metilbenzamida (C76)

Figure img0154
[000230] Isolated as an off-white powder (): mp 130-132°C; 1H NMR (400 MHz, DMSO-d6) δ 8.49 (br d, J = 8 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.52-6.59 ( m, 2H), 5.36 (br s, 2H), 4.31 (m, 1H), 2.13-2.23 (m, 2H), 1.91-2.02 (m, 2H), 1.58-1.69 (m, 2H); IR (thin film) 3447 (w), 3334 (m), 3283 (m), 2991 (w), 2942 (w), 2861 (w), 1618 (s), 1601 (s), 1541 (s), 1476 (m), 1428 (m) cm-1; ESIMS m/z 225 ([M+H]+).Example 24: Preparation of 5-amino-2-chloro-N-(3,3-difluorocyclobutyl)-N-methylbenzamide (C76)
Figure img0154

[000231] A uma solução de 2-cloro-N-(3,3-difluorociclobutil)-N-metil- 5-nitrobenzamida (C82) (0,513 g, 1,68 mmol) em acetato de etila (10 mL) em uma manta de nitrogênio foi adicionado paládio em carbono (0,179 g, 0,0840 mmol). A reação foi colocada em um balão de hidrogênio e agitada vigorosamente por 5 horas. A reação foi filtrada através de Celite®, lavando com acetato de etila. Os filtrados foram concentrados para obter o composto do título como um sólido branco (0,394 g, 85%): 1H RMN (400 MHz, CDCl3) δ rotâmeros 7,14 (dd, J = 8,6, 5,6 Hz, 1H), 6,64 (ddd, J = 8,5, 7,5, 2,8 Hz, 1H), 6,54 (dd, J = 14,9, 2,8 Hz, 1H), 5,03 - 4,82 (m, 0,5 H), 4,22 - 4,06 (m, 0,5 H), 3,77 (s, 2H), 3,09 (s, 1,5 H), 3,04 - 2,91 (m, 1 H), 2,85 (s, 1,5 H), 2,92 - 2,59 (m, 3H); 19F RMN (376 MHz, CDCl3) δ rotâmeros -83,92 (d, J = 199,2 Hz), -84,69 (d, J = 201,6 Hz), -99,42 (d, J = 201,6 Hz), -99,78 (d, J = 199,1 Hz); ESIMS m/z 275 ([M+H]+).Exemplo 25: Preparação de 5-amino-2-cloro-N-(3-cianociclopentil) benzamida (C77)

Figure img0155
[000231] To a solution of 2-chloro-N-(3,3-difluorocyclobutyl)-N-methyl-5-nitrobenzamide (C82) (0.513 g, 1.68 mmol) in ethyl acetate (10 mL) in a nitrogen blanket was added palladium on carbon (0.179 g, 0.0840 mmol). The reaction was placed in a balloon of hydrogen and stirred vigorously for 5 hours. The reaction was filtered through Celite®, washing with ethyl acetate. The filtrates were concentrated to obtain the title compound as a white solid (0.394 g, 85%): 1H NMR (400 MHz, CDCl3) δ rotamers 7.14 (dd, J = 8.6, 5.6 Hz, 1H ), 6.64 (ddd, J = 8.5, 7.5, 2.8 Hz, 1H), 6.54 (dd, J = 14.9, 2.8 Hz, 1H), 5.03 - 4.82 (m, 0.5H), 4.22 - 4.06 (m, 0.5H), 3.77 (s, 2H), 3.09 (s, 1.5H), 3 .04 - 2.91 (m, 1H), 2.85 (s, 1.5H), 2.92 - 2.59 (m, 3H); 19F NMR (376 MHz, CDCl3) δ rotamers -83.92 (d, J = 199.2 Hz), -84.69 (d, J = 201.6 Hz), -99.42 (d, J = 201 0.6 Hz), -99.78 (d, J = 199.1 Hz); ESIMS m/z 275 ([M+H]+).Example 25: Preparation of 5-amino-2-chloro-N-(3-cyanocyclopentyl)benzamide (C77)
Figure img0155

[000232] Cloridrato de 1-etil-3-(3-dimetilaminopropil)-carbodiimida (0,490g, 2,50 mmol) e 4-dimetilaminopiridina (0,270 g, 2,20 mmol) foram adicionados sequencialmente a uma mistura agitada de ácido 5- amino-2-clorobenzoico (0,290 g, 1,70 mmol), cloridrato de 3-aminoci- clopentanocarbonitrila (0,250 g, 1,70 mmol) e trietilamina (0,280 mL, 2,00 mmol) em diclorometano (11 mL) a 23°C. A solução marrom amarelada clara homogênea resultante foi agitada a 23°C por 72 horas. A mistura de reação foi concentrada e o resíduo foi purificado por croma- tografia de coluna de flash de fase reversa usando 5-100% de acetoni- trila/água como eluente para fornecer o composto do título como um pó esbranquiçado (0,350 g, 78%): pf 117-119°C; 1H RMN (400 MHz, DMSO-d6) δ 8,46 (br d, J = 7 Hz, 1H), 7,05 (d, J = 8,2 Hz, 1H), 6,536,59 (m, 2H), 5,37 (br s, 2H), 4,19 (m, 1H), 3,01 (p, J = 8 Hz, 1H), 2,39 (m, 1H), 2,02 (m, 1H), 1,83-1,95 (m, 2H), 1,61-1,78 (m, 2H); IR (película fina) 3444 (m), 3360 (m), 3237 (m), 3064 (w), 2951 (w), 2875 (w), 2238 (m), 1626 (s), 1599 (s), 1577 (m), 1544 (s), 1475 (s), 1437 (s) cm- 1; ESIMS m/z 264 ([M+H]+).[000232] 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.490g, 2.50mmol) and 4-dimethylaminopyridine (0.270g, 2.20mmol) were sequentially added to a stirred mixture of acid. - amino-2-chlorobenzoic (0.290 g, 1.70 mmol), 3-aminocyclopentanecarbonitrile hydrochloride (0.250 g, 1.70 mmol) and triethylamine (0.280 ml, 2.00 mmol) in dichloromethane (11 ml) a 23°C. The resulting homogeneous light yellowish brown solution was stirred at 23°C for 72 hours. The reaction mixture was concentrated and the residue was purified by reverse phase flash column chromatography using 5-100% acetonitrile/water as eluent to furnish the title compound as an off-white powder (0.350 g, 78 %): mp 117-119°C; 1H NMR (400 MHz, DMSO-d6) δ 8.46 (br d, J = 7 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.536.59 (m, 2H) , 5.37 (br s, 2H), 4.19 (m, 1H), 3.01 (p, J = 8 Hz, 1H), 2.39 (m, 1H), 2.02 (m, 1H ), 1.83-1.95 (m, 2H), 1.61-1.78 (m, 2H); IR (thin film) 3444 (m), 3360 (m), 3237 (m), 3064 (w), 2951 (w), 2875 (w), 2238 (m), 1626 (s), 1599 (s), 1577(m), 1544(s), 1475(s), 1437(s) cm-1; ESIMS m/z 264 ([M+H]+).

[000233] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 25: 5-Amino-2-cloro-N-(4,4-difluorociclo-hexil)benzamida (C78)

Figure img0156
[000233] The following compounds were prepared in a manner similar to the procedure described in Example 25: 5-Amino-2-chloro-N-(4,4-difluorocyclohexyl)benzamide (C78)
Figure img0156

[000234] Isolado como um pó cinza (0,560 g, 67%): pf 132°C (dec.); 1H RMN (400 MHz, DMSO-d6) δ 8,28 (br d, J = 8 Hz, 1H), 7,04 (d, J = 8 Hz, 1H), 6,51-6,60 (m, 2H), 5,37 (br s, 2H), 3,90 (m, 1H), 1,80-2,09 (m, 6H), 1,50-1,63 (m, 2H); IR (película fina) 3430 (w), 3298 (m), 2948 (w), 1634 (s), 1602 (m), 1579 (m), 1533 (s), 1478 (m) cm-1; ESIMS m/z 289 ([M+H]+). Exemplo 26: Preparação de 2-cloro-N-ciclopropil-5-nitrobenzamida (C79)

Figure img0157
[000234] Isolated as a gray powder (0.560 g, 67%): mp 132°C (dec.); 1H NMR (400 MHz, DMSO-d6) δ 8.28 (br d, J = 8 Hz, 1H), 7.04 (d, J = 8 Hz, 1H), 6.51-6.60 (m, 2H), 5.37 (br s, 2H), 3.90 (m, 1H), 1.80-2.09 (m, 6H), 1.50-1.63 (m, 2H); IR (thin film) 3430 (w), 3298 (m), 2948 (w), 1634 (s), 1602 (m), 1579 (m), 1533 (s), 1478 (m) cm-1; ESIMS m/z 289 ([M+H]+). Example 26: Preparation of 2-chloro-N-cyclopropyl-5-nitrobenzamide (C79)
Figure img0157

[000235] Ácido 2-cloro-5-nitrobenzoico (0,250 g, 1,24 mmol) e 4- dimetilaminopiridina (0,197 g, 1,61 mmol) foram adicionados sequen-cialmente a uma mistura agitada de ciclopropanamina (0,103 mL, 1,49 mmol) e 1-etil-3-(3-dimetilaminopropil)-carbodi-imida (0,357 g, 1,86 mmol) em 1,2-dicloroetano (12 mL) à temperatura ambiente. A reação foi agitada à temperatura ambiente por 20 horas. A reação foi diluída com diclorometano e lavada com bicarbonato de sódio aquoso saturado e ácido clorídrico (1 N). A fase orgânica secou sobre sulfato de magnésio, foi filtrada e concentrada para fornecer o composto do título como um sólido branco (0,142 g, 45%): pf 173-176°C;1H RMN (400 MHz, CDCl3) δ 8,49 (d,J = 2,7 Hz, 1H), 8,21 (dd,J = 8,8, 2,7 Hz, 1H), 7,59 (d,J = 8,8 Hz, 1H), 6,26 (s, 1H), 3,02 - 2,89 (m, 1H), 0,98 -0,90 (m, 2H), 0,72 - 0,64 (m, 2H); ESIMS m/z 241 ([M+H]+).[000235] 2-Chloro-5-nitrobenzoic acid (0.250 g, 1.24 mmol) and 4-dimethylaminopyridine (0.197 g, 1.61 mmol) were added sequentially to a stirred mixture of cyclopropanamine (0.103 ml, 1, 49 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (0.357 g, 1.86 mmol) in 1,2-dichloroethane (12 mL) at room temperature. The reaction was stirred at room temperature for 20 hours. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and hydrochloric acid (1N). The organic phase dried over magnesium sulfate, filtered and concentrated to furnish the title compound as a white solid (0.142 g, 45%): mp 173-176°C; 1H NMR (400 MHz, CDCl 3 ) δ 8.49 (d,J = 2.7 Hz, 1H), 8.21 (dd,J = 8.8, 2.7 Hz, 1H), 7.59 (d,J = 8.8 Hz, 1H), 6 .26 (s, 1H), 3.02 - 2.89 (m, 1H), 0.98 -0.90 (m, 2H), 0.72 - 0.64 (m, 2H); ESIMS m/z 241 ([M+H]+).

[000236] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 26: N-Ciclopropil-5-nitro-2-(trifluorometil)benzamida (C80)

Figure img0158
[000236] The following compounds were prepared in a manner similar to the procedure described in Example 26: N-Cyclopropyl-5-nitro-2-(trifluoromethyl)benzamide (C80)
Figure img0158

[000237] Isolado como um sólido branco (0,189 g, 31%): 1H RMN (400 MHz, CDCl3) δ 8,40 - 8,33 (m, 2H), 7,93 - 7,87 (m, 1H), 5,98 (s, 1H), 2,96 - 2,88 (m, 1H), 0,96 - 0,89 (m, 2H), 0,70 - 0,64 (m, 2H); EIMS m/z 274 ([M]+).Exemplo 27: Preparação de 2-cloro-N-(1-cianociclopropil)-5- nitrobenzamida (C81)

Figure img0159
[000237] Isolated as a white solid (0.189 g, 31%): 1H NMR (400 MHz, CDCl 3 ) δ 8.40 - 8.33 (m, 2H), 7.93 - 7.87 (m, 1H) , 5.98 (s, 1H), 2.96 - 2.88 (m, 1H), 0.96 - 0.89 (m, 2H), 0.70 - 0.64 (m, 2H); EIMS m/z 274 ([M]+).Example 27: Preparation of 2-chloro-N-(1-cyanocyclopropyl)-5-nitrobenzamide (C81)
Figure img0159

[000238] Ácido 2-cloro-5-nitrobenzoico (0,500 g, 2,48 mmol), 4-dime- tilaminopiridina (0,394 mL, 3,22 mmol) foram adicionados a uma solução de cloridrato de 1-aminociclopropanocarbonitrila (0,353 g, 2,98 mmol), dietilisopropiletilamina (0,520 mL, 2,98 mmol) e 1-etil-3-(3-di- metilaminopropil)-carbodiimida (0,713 g, 3,72 mmol) em 1,2-dicloroetano (9,92 mL) à temperatura ambiente. A reação foi agitada em temperatura ambiente durante a noite. A mistura de reação foi diluída com acetato de etila e lavada com bicarbonato de sódio aquoso saturado e seguida por ácido clorídrico (1 N). As fases orgânicas foram secas sobre sulfato de magnésio, filtradas e concentradas para fornecer o composto do título como um sólido branco (0,444 g, 64%): 1H RMN (400 MHz, DMSO-d6) δ 9,62 (s, 1H), 8,37 (d, J = 2,7 Hz, 1H), 8,31 (dd, J = 8,8, 2,8 Hz, 1H), 7,85 (d, J = 8,8 Hz, 1H), 1,59 (dd, J = 8,3, 5,4 Hz, 2H), 1,34 (dd, J = 8,4, 5,5 Hz, 2H); IR (película fina) 3271, 3103, 2247, 1664 cm-1; ESIMS m/z 266 ([M+H]+).[000238] 2-Chloro-5-nitrobenzoic acid (0.500 g, 2.48 mmol), 4-dimethylaminopyridine (0.394 mL, 3.22 mmol) were added to a solution of 1-aminocyclopropanecarbonitrile hydrochloride (0.353 g, 2.98 mmol), diethylisopropylethylamine (0.520 mL, 2.98 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (0.713 g, 3.72 mmol) in 1,2-dichloroethane (9, 92 ml) at room temperature. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and followed by hydrochloric acid (1N). The organic phases were dried over magnesium sulfate, filtered and concentrated to furnish the title compound as a white solid (0.444 g, 64%): 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H) , 8.37 (d, J = 2.7 Hz, 1H), 8.31 (dd, J = 8.8, 2.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 1.59 (dd, J = 8.3, 5.4 Hz, 2H), 1.34 (dd, J = 8.4, 5.5 Hz, 2H); IR (thin film) 3271, 3103, 2247, 1664 cm-1; ESIMS m/z 266 ([M+H]+).

[000239] Os seguintes compostos foram preparados de maneira seme-lhante ao procedimento descrito no Exemplo 27: 2-Cloro-N-(3,3-difluorociclobutil)-5-nitrobenzamida (C82)

Figure img0160
[000239] The following compounds were prepared in a manner similar to the procedure described in Example 27: 2-Chloro-N-(3,3-difluorocyclobutyl)-5-nitrobenzamide (C82)
Figure img0160

[000240] Isolado como uma espuma branca (0,103 g, 71%): 1H RMN (400 MHz, Acetona-d6) δ 8,36 (d, J = 2,8 Hz, 1H), 8,30 (dd, J = 8,8, 2,8 Hz, 1H), 8,26 (s, 1H), 7,79 (d, J = 8,7 Hz, 1H), 4,41 (dd, J = 15,0, 7,3 Hz, 1H), 3,16 - 2,97 (m, 2H), 2,88 - 2,77 (m, 2H); ESIMS m/z 291 ([M+H]+).Exemplo 28: Preparação de 2-cloro-N-(3,3-difluorociclobutil)-N-metil-5- nitrobenzamida (C83)

Figure img0161
[000240] Isolated as a white foam (0.103 g, 71%): 1H NMR (400 MHz, Acetone-d6) δ 8.36 (d, J = 2.8 Hz, 1H), 8.30 (dd, J = 8.8, 2.8 Hz, 1H), 8.26 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 4.41 (dd, J = 15.0, 7.3 Hz, 1H), 3.16 - 2.97 (m, 2H), 2.88 - 2.77 (m, 2H); ESIMS m/z 291 ([M+H]+).Example 28: Preparation of 2-chloro-N-(3,3-difluorocyclobutyl)-N-methyl-5-nitrobenzamide (C83)
Figure img0161

[000241] A uma solução de 2-cloro-N-(3,3-difluorociclobutil)-5- nitrobenzamida (C82) (0,490 g, 1,69 mmol) em N,N-dimetilforamida seco (8 mL) resfriado em um banho-maria gelado foi adicionado hidre- to de sódio (0,0940 g, 2,36 mmol). A solução foi agitada durante 30 minutos e, iodometano (0,264 mL, 4,21 mmol) foi adicionado. A mistura de reação foi agitada por 3 horas. A mistura de reação foi refrigerada em banho-maria gelado e extinta por adição lenta de água. A reação foi diluída com acetato etila (30 mL). A camada orgânica foi lavada com água (2 x 20 mL) e salmoura (20 mL). A camada orgânica foi vertida através de um separador de fase para seco e concentrado para fornecer o composto do título como um sólido amarelo claro (0,513 g, quant): 1H RMN (400 MHz, CDCI3) δ rotâmeros 8,29 - 8,13 (m, 2H), 7,66 - 7,58 (m, 1H), 5,00 - 4,85 (m, 0,5 H), 4,05 - 3,92 (m, 0,5 H), 3,16 (s, 1,5 H), 3,10 - 2,95 (m, 1H), 2,87 (s, 1,5 H) 2,95 - 2,66 (m, 2H); 19F RMN (376 MHz, CDCl3) δ rotâmeros -84,01 (d, J = 199,7 Hz), - 84,85 (d, J = 202,6 Hz), -99,36 (d, J = 202,5 Hz), -99,67 (d, J = 199,7 Hz); ESIMS m/z 305 ([M+H]+).[000241] To a solution of 2-chloro-N-(3,3-difluorocyclobutyl)-5-nitrobenzamide (C82) (0.490 g, 1.69 mmol) in dry N,N-dimethylforamide (8 mL) cooled in a ice-cold water bath was added sodium hydride (0.0940 g, 2.36 mmol). The solution was stirred for 30 minutes and iodomethane (0.264 mL, 4.21 mmol) was added. The reaction mixture was stirred for 3 hours. The reaction mixture was cooled in an ice-cold water bath and quenched by slow addition of water. The reaction was diluted with ethyl acetate (30 mL). The organic layer was washed with water (2 x 20 mL) and brine (20 mL). The organic layer was poured through a phase separator to dry and concentrated to furnish the title compound as a pale yellow solid (0.513 g, quant): 1H NMR (400 MHz, CDCl3) δ rotamers 8.29 - 8.13 (m, 2H), 7.66 - 7.58 (m, 1H), 5.00 - 4.85 (m, 0.5H), 4.05 - 3.92 (m, 0.5H) , 3.16 (s, 1.5H), 3.10 - 2.95 (m, 1H), 2.87 (s, 1.5H) 2.95 - 2.66 (m, 2H); 19F NMR (376 MHz, CDCl3) δ rotamers -84.01 (d, J = 199.7 Hz), - 84.85 (d, J = 202.6 Hz), -99.36 (d, J = 202 0.5 Hz), -99.67 (d, J = 199.7 Hz); ESIMS m/z 305 ([M+H]+).

[000242] As seguintes moléculas na Tabela 1 podem ser preparadas de acordo com os procedimentos divulgados acima.Tabela P1: Estrutura e método de preparação para as moléculas pro-féticas

Figure img0162
Figure img0163
Figure img0164
Figure img0165
Figure img0166
Figure img0167
Figure img0168
Figure img0169
Figure img0170
Prep* significa preparar de acordo com o Exemplo ou Esquema[000242] The following molecules in Table 1 can be prepared according to the procedures disclosed above.Table P1: Structure and method of preparation for the prophetic molecules
Figure img0162
Figure img0163
Figure img0164
Figure img0165
Figure img0166
Figure img0167
Figure img0168
Figure img0169
Figure img0170
Prep* means to prepare according to Example or Scheme

[000243] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 2:Ácido trans-3-(4-Bromo-3-clorofenil)-2,2-diclorociclopropano-1-carboxí- lico (C84)

Figure img0171
[000243] The following compounds were prepared in a manner similar to the procedure described in Example 2: trans-3-(4-Bromo-3-chlorophenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (C84)
Figure img0171

[000244] Isolado como um sólido marrom (0,186 g, 60%): 1H RMN (400 MHz, CDCI3) δ 7,63 (d, J = 8,3 Hz, 1H), 7,40 - 7,32 (m, 1H), 7,04 (ddd, J = 8,3, 2,2, 0,7 Hz, 1H), 3,42 (d, J = 8,3 Hz, 1H), 2,86 (d, J = 8,3 Hz, 1H); 13C RMN (101 MHz, CDCl3) δ 171,39, 134,91, 133,89, 133,08, 130,54, 128,16, 122,61, 61,39, 39,70, 37,14; ESIMS m/z 342,8 ([M-H]-).Ácido trans-3-(4-Bromo-3,5-difluorofenil)-2,2-diciclopropano-1-carboxí- lico (C85)

Figure img0172
[000244] Isolated as a brown solid (0.186 g, 60%): 1H NMR (400 MHz, CDCl 3 ) δ 7.63 (d, J = 8.3 Hz, 1H), 7.40 - 7.32 (m , 1H), 7.04 (ddd, J = 8.3, 2.2, 0.7 Hz, 1H), 3.42 (d, J = 8.3 Hz, 1H), 2.86 (d, J = 8.3 Hz, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 171.39, 134.91, 133.89, 133.08, 130.54, 128.16, 122.61, 61.39, 39.70, 37.14; ESIMS m/z 342.8 ([MH]-).trans-3-(4-Bromo-3,5-difluorophenyl)-2,2-dicyclopropane-1-carboxylic acid (C85)
Figure img0172

[000245] Isolado como um sólido branco (2,13 g, 72%): pf 178,3 - 188,6°C; 1H RMN (400 MHz, CDCh) δ 6,90 (d, J = 7,1 Hz, 2H), 3,43 (d, J = 8,2 Hz, 1H), 2,86 (d, J = 8,2 Hz, 1H); 19F RMN (376 MHz, CDCh) δ -103,87; ESIMS m/z 344,7 ([M-H]-).Ácido trans-3-(4-bromo-3-flúor-5-metoxifenil)-2,2-diclorociclopropano- 1-carboxílico (C86)

Figure img0173
[000245] Isolated as a white solid (2.13 g, 72%): mp 178.3 - 188.6°C; 1H NMR (400 MHz, CDCh) δ 6.90 (d, J = 7.1 Hz, 2H), 3.43 (d, J = 8.2 Hz, 1H), 2.86 (d, J = 8 .2 Hz, 1H); 19F NMR (376 MHz, CDCh) δ -103.87; ESIMS m/z 344.7 ([MH]-).trans-3-(4-Bromo-3-fluoro-5-methoxyphenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (C86)
Figure img0173

[000246] Isolado como um sólido oleoso (0,43 g, 37%): 1H RMN (400 MHz, CDCl3) δ 6,70 - 6,64 (m, 1H), 6,61 (d, J = 1,6 Hz, 1H), 3,95 (s, 3H), 3,44 (d, J = 8,3 Hz, 1H), 2,86 (d, J = 8,3 Hz, 1H); 19F RMN (376 MHz, CDCl3) δ -104,22; ESIMS m/z 356,7 ([M-H]-).Ácido trans-3-(3-Bromo-5-flúor-4-metoxifenil)- 2,2-diclorociclopropano- 1-carboxílico (C87)

Figure img0174
[000246] Isolated as an oily solid (0.43 g, 37%): 1H NMR (400 MHz, CDCl 3 ) δ 6.70 - 6.64 (m, 1H), 6.61 (d, J = 1, 6Hz, 1H), 3.95 (s, 3H), 3.44 (d, J = 8.3 Hz, 1H), 2.86 (d, J = 8.3 Hz, 1H); 19F NMR (376 MHz, CDCl 3 ) δ -104.22; ESIMS m/z 356.7 ([MH]-). trans-3-(3-Bromo-5-fluoro-4-methoxyphenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (C87)
Figure img0174

[000247] Isolado como um óleo marrom (0,24 g, 65%): 1H RMN (400 MHz, CDCl3) δ 7,24 (d, J = 7,9 Hz, 1H), 6,87 (d, J = 11,3 Hz, 1H), 3,91 (d, J = 3,8 Hz, 3H), 3,44 (d, J = 8,3 Hz, 1H), 2,80 (d, J = 8,3 Hz, 1H);19F RMN (376 MHz, CDCI3) δ -135,11; ESIMS m/z 356,7 ([M-H]-).Ácido trans-2,2-Dicloro-3-(3-cloro-5-(difluorometil)fenil)ciclopropano-1- carboxílico (C88)

Figure img0175
[000247] Isolated as a brown oil (0.24 g, 65%): 1H NMR (400 MHz, CDCl 3 ) δ 7.24 (d, J = 7.9 Hz, 1H), 6.87 (d, J = 11.3 Hz, 1H), 3.91 (d, J = 3.8 Hz, 3H), 3.44 (d, J = 8.3 Hz, 1H), 2.80 (d, J = 8 .3Hz, 1H);19F NMR (376MHz, CDCl3 ) δ -135.11; ESIMS m/z 356.7 ([MH]-). trans-2,2-Dichloro-3-(3-chloro-5-(difluoromethyl)phenyl)cyclopropane-1-carboxylic acid (C88)
Figure img0175

[000248] Isolado como um sólido esbranquiçado (2,6 g, 63%): 1H RMN (300 MHz, CDCl3) sinal de COOH ausente δ 7,49 (s, 1H), 7,38 (s, 1H), 7,30 (s, 1H), 6,63 (t, J = 56,0 Hz, 1H), 3,50 (d, J = 8,4 Hz, 1H), 2,91 (d, J = 8,0 Hz, 1H); 19F RMN (282 MHz, CDCl3) δ 112,04; ESIMS m/z 313 ([M-H]-).Ácido trans-2,2-dicloro-3-(4-cloro-3-(difluorometil)fenil)ciclopropano- carboxílico (C89)

Figure img0176
[000248] Isolated as an off-white solid (2.6 g, 63%): 1H NMR (300 MHz, CDCl3) COOH signal absent δ 7.49 (s, 1H), 7.38 (s, 1H), 7 .30 (s, 1H), 6.63 (t, J = 56.0 Hz, 1H), 3.50 (d, J = 8.4 Hz, 1H), 2.91 (d, J = 8. 0Hz, 1H); 19F NMR (282 MHz, CDCl 3 ) δ 112.04; ESIMS m/z 313 ([MH]-).trans-2,2-dichloro-3-(4-chloro-3-(difluoromethyl)phenyl)cyclopropane-carboxylic acid (C89)
Figure img0176

[000249] Isolado como um sólido esbranquiçado (6,2 g, 69%): 1H RMN (400 MHz, CDCl3) δ 10,5 (br s, 1H), 7,55 (s, 1H), 7,46 (d, J = 8,0 Hz, 1H), 7,34 (d, J = 8,4 Hz, 1H), 6,95 (t, J = 54,8 Hz, 1H), 3,50 (d, J = 8,4 Hz, 1H), 2,91 (d, J = 8,4 Hz, 1H); 19F RMN (376 MHz, CDCl3) δ 115,52; ESIMS m/z 313 ([M-H]-).Ácido trans-2,2-dicloro-3-(3-(difluorometil)-5-fluorofenil)ciclopropano- carboxílico (C90)

Figure img0177
[000249] Isolated as an off-white solid (6.2 g, 69%): 1H NMR (400 MHz, CDCl 3 ) δ 10.5 (br s, 1H), 7.55 (s, 1H), 7.46 ( d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 54.8 Hz, 1H), 3.50 (d, J = 8.4 Hz, 1H), 2.91 (d, J = 8.4 Hz, 1H); 19F NMR (376 MHz, CDCl 3 ) δ 115.52; ESIMS m/z 313 ([MH]-). trans-2,2-dichloro-3-(3-(difluoromethyl)-5-fluorophenyl)cyclopropane-carboxylic acid (C90)
Figure img0177

[000250] Isolado como um sólido esbranquiçado (5,00 g, 38%): 1H RMN (400 MHz, CDCI3) sinal de COOH ausente δ 7,23 - 7,21 (m, 2H), 7,11 (d, J = 8,8 Hz, 1H), 6,64 (t, J = 55,6 Hz, 1H), 3,51 (d, J = 8,4 Hz, 1H), 2,91 (d, J = 8,0 Hz, 1H); 19F RMN (376 MHz, CDCl3) δ 110,37; ESIMS m/z 297,19 ([M-H]-).Ácido trans-2,2-dicloro-3-(3-(difluorometil)-4-fluorofenil)ciclopropano- carboxílico (C91)

Figure img0178
[000250] Isolated as an off-white solid (5.00 g, 38%): 1H NMR (400 MHz, CDCl3) COOH signal absent δ 7.23 - 7.21 (m, 2H), 7.11 (d, J = 8.8 Hz, 1H), 6.64 (t, J = 55.6 Hz, 1H), 3.51 (d, J = 8.4 Hz, 1H), 2.91 (d, J = 8.0Hz, 1H); 19F NMR (376 MHz, CDCl 3 ) δ 110.37; ESIMS m/z 297.19 ([MH]-). trans-2,2-dichloro-3-(3-(difluoromethyl)-4-fluorophenyl)cyclopropane-carboxylic acid (C91)
Figure img0178

[000251] Isolado como um sólido esbranquiçado (6,0 g, 77%): 1H RMN (400 MHz, CDCl3) sinal de COOH ausente δ 7,49 (d, J = 6,0 Hz, 1H), 7,40 (br s, 1H), 7,17 (t, J = 9,2 Hz, 1H), 6,90 (t, J = 54,8 Hz, 1H), 3,49 (d, J = 8,0 Hz, 1H), 2,89 (d, J = 8,4 Hz, 1H); 19F RMN (376 MHz, CDCl3) δ 114,47, 119,69; ESIMS m/z 297 ([M-H]-).Ácido trans-2,2-dicloro-3-(3-cloro-4-(difluorometil)fenil)ciclopropano- carboxílico (C92)

Figure img0179
[000251] Isolated as an off-white solid (6.0 g, 77%): 1H NMR (400 MHz, CDCl3) COOH signal absent δ 7.49 (d, J = 6.0 Hz, 1H), 7.40 (br s, 1H), 7.17 (t, J = 9.2 Hz, 1H), 6.90 (t, J = 54.8 Hz, 1H), 3.49 (d, J = 8.0 Hz, 1H), 2.89 (d, J = 8.4 Hz, 1H); 19F NMR (376 MHz, CDCl 3 ) δ 114.47, 119.69; ESIMS m/z 297 ([MH]-). trans-2,2-dichloro-3-(3-chloro-4-(difluoromethyl)phenyl)cyclopropane-carboxylic acid (C92)
Figure img0179

[000252] Isolado como um sólido esbranquiçado (3,5 g, 42%): 1H RMN (400 MHz, CDCl3) sinal de COOH ausente δ 7,68 (d, J = 7,6 Hz, 1H), 7,35 (s, 1H), 7,29 (d, J = 8,4 Hz, 1H), 6,94 (t, J = 54,8 Hz, 1H), 3,48 (d, J = 8,4 Hz, 1H), 2,91 (d, J = 8,4 Hz, 1H); 19F RMN (376 MHz, CDCl3) δ 115,46; ESIMS m/z 313 ([M-H]-).Ácido trans-2,2-dicloro-3-(4-(difluorometil)-3-fluorofenil)ciclopropano- carboxílico (C93)

Figure img0180
[000252] Isolated as an off-white solid (3.5 g, 42%): 1H NMR (400 MHz, CDCl3) COOH signal absent δ 7.68 (d, J = 7.6 Hz, 1H), 7.35 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 54.8 Hz, 1H), 3.48 (d, J = 8.4 Hz , 1H), 2.91 (d, J = 8.4 Hz, 1H); 19F NMR (376 MHz, CDCl 3 ) δ 115.46; ESIMS m/z 313 ([MH]-). trans-2,2-dichloro-3-(4-(difluoromethyl)-3-fluorophenyl)cyclopropane-carboxylic acid (C93)
Figure img0180

[000253] Isolado como um sólido esbranquiçado (4,4 g, 77%): 1H RMN (400 MHz, CDCl3) δ 7,62 (t, J = 7,6 Hz, 1H), 7,18 (d, J = 7,6 Hz, 1H), 7,06 (d, J = 10,0 Hz, 1H), 6,89 (t, J = 54,8 Hz, 1H), 3,50 (d, J = 8,4 Hz, 1H), 2,90 (d, J = 8,4 Hz, 1H); 19F RMN (376 MHz, CDCl3) δ 114,42, 118,63; ESIMS m/z 297,15 ([M-H]-).Ácido trans-2,2-dicloro-3-(3-(difluorometil)fenil)ciclopropanocarboxílico (C94)

Figure img0181
[000253] Isolated as an off-white solid (4.4 g, 77%): 1H NMR (400 MHz, CDCl 3 ) δ 7.62 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 10.0 Hz, 1H), 6.89 (t, J = 54.8 Hz, 1H), 3.50 (d, J = 8 .4 Hz, 1H), 2.90 (d, J = 8.4 Hz, 1H); 19F NMR (376 MHz, CDCl 3 ) δ 114.42, 118.63; ESIMS m/z 297.15 ([MH]-).trans-2,2-dichloro-3-(3-(difluoromethyl)phenyl)cyclopropanecarboxylic acid (C94)
Figure img0181

[000254] Isolado como um sólido esbranquiçado (6,2 g, 53%): 1H RMN (300 MHz, CDCl3) δ 7,49 (br s, 2H), 7,41 (br s, 2H), 6,66 (t, J = 56,0 Hz, 1H), 3,53 (d, J = 8,4 Hz, 1H), 2,92 (d, J = 8,0 Hz, 1H); 19F RMN (282 MHz, CDCl3) δ 111,20; ESIMS m/z 279,20 ([M-H]-).Ácido trans-2,2-Dicloro-3-(4-(difluorometil)fenil)ciclopropanocarboxílico (C95)

Figure img0182
[000254] Isolated as an off-white solid (6.2 g, 53%): 1H NMR (300 MHz, CDCl 3 ) δ 7.49 (br s, 2H), 7.41 (br s, 2H), 6.66 (t, J = 56.0 Hz, 1H), 3.53 (d, J = 8.4 Hz, 1H), 2.92 (d, J = 8.0 Hz, 1H); 19F NMR (282 MHz, CDCl 3 ) δ 111.20; ESIMS m/z 279.20 ([MH]-). trans-2,2-Dichloro-3-(4-(difluoromethyl)phenyl)cyclopropanecarboxylic acid (C95)
Figure img0182

[000255] Isolado como um sólido esbranquiçado (7,00 g, 61%): 1H RMN (300 MHz, CDCl3) δ 7,53 (d, J = 8,0 Hz, 2H), 7,37 (d, J = 8,0 Hz, 2H), 6,66 (t, J = 56,4 Hz, 1H), 3,52 (d, J = 8,4 Hz, 1H), 2,92 (d, J = 8,0 Hz, 1H); 19F RMN (282 MHz, CDCl3) δ 112,20; ESIMS m/z 279,30 ([MH]-).[000255] Isolated as an off-white solid (7.00 g, 61%): 1H NMR (300 MHz, CDCl 3 ) δ 7.53 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 6.66 (t, J = 56.4 Hz, 1H), 3.52 (d, J = 8.4 Hz, 1H), 2.92 (d, J = 8 0.0Hz, 1H); 19F NMR (282 MHz, CDCl 3 ) δ 112.20; ESIMS m/z 279.30 ([MH]-).

[000256] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 4: trans-1-Cloro-3-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)-5-(difluoro- metil)benzeno (C96)

Figure img0183
[000256] The following compounds were prepared in a manner similar to the procedure described in Example 4: trans-1-Chloro-3-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)-5-(difluoro- methyl)benzene (C96)
Figure img0183

[000257] Isolado como um líquido amarelo (11,5 g, 69%): 1H RMN (300 MHz, CDCl3): δ 7,47 (s, 2H), 7,39 (s, 1H), 7,28 (d, J = 8,7 Hz, 2H), 6,93 (d, J = 8,7 Hz, 2H), 6,64 (t, J = 56,1 Hz, 1H), 3,83 (s, 3H), 3,16 (q, J = 8,7 Hz, 2H).trans-1-Cloro-4-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)-2-(difluoro- metil)benzeno (C97)

Figure img0184
[000257] Isolated as a yellow liquid (11.5 g, 69%): 1H NMR (300 MHz, CDCl3): δ 7.47 (s, 2H), 7.39 (s, 1H), 7.28 ( d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.64 (t, J = 56.1 Hz, 1H), 3.83 (s, 3H), 3.16 (q, J = 8.7 Hz, 2H). trans-1-Chloro-4-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)-2-(difluoromethyl) )benzene (C97)
Figure img0184

[000258] Isolado como um sólido amarelo pálido (10,7 g, 83%): 1H RMN (400 MHz, CDCI3) δ 7,65 (s, 1H), 7,46 - 7,41 (m, 2H), 7,28 (d, J = 8,4 Hz, 2H), 7,10 - 6,83 (m, 3H), 3,83 (s, 3H), 3,18 - 3,13 (m, 2H). trans-1-(2,2-Dicloro-3-(4-metoxifenil)ciclopropil)-3-(difluorometil)-5-flu- orobenzeno (C98)

Figure img0185
[000258] Isolated as a pale yellow solid (10.7 g, 83%): 1H NMR (400 MHz, CDCl 3 ) δ 7.65 (s, 1H), 7.46 - 7.41 (m, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.10 - 6.83 (m, 3H), 3.83 (s, 3H), 3.18 - 3.13 (m, 2H) . trans-1-(2,2-Dichloro-3-(4-methoxyphenyl)cyclopropyl)-3-(difluoromethyl)-5-fluorobenzene (C98)
Figure img0185

[000259] Isolado como um sólido esbranquiçado (16,5 g, 64%): 1H RMN (400 MHz, CDCl3) δ 7,29 (d, J = 8,8 Hz, 2H), 7,20 (d, J = 8,8 Hz, 2H), 6,93 (d, J = 8,8 Hz, 2H), 6,65 (t, J = 56,0 Hz, 2H), 3,83 (s, 3H), 3,16 (s, 2H).trans-4-(2,2-Dicloro-3-(4-metoxifenil)ciclopropil)-2-(difluorometil)-1- fluorobenzeno (C99)

Figure img0186
[000259] Isolated as an off-white solid (16.5 g, 64%): 1H NMR (400 MHz, CDCl 3 ) δ 7.29 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.65 (t, J = 56.0 Hz, 2H), 3.83 (s, 3H), 3.16 (s, 2H). trans-4-(2,2-Dichloro-3-(4-methoxyphenyl)cyclopropyl)-2-(difluoromethyl)-1-fluorobenzene (C99)
Figure img0186

[000260] Isolado como um sólido esbranquiçado (10,0 g, 55%): ESIMS m/z 374 ([M+H]+).trans-2-Cloro-4-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)-1-(difluorometil)benzeno (C100)

Figure img0187
[000260] Isolated as an off-white solid (10.0 g, 55%): ESIMS m/z 374 ([M+H]+).trans-2-Chloro-4-(2,2-dichloro-3-( 4-methoxyphenyl)cyclopropyl)-1-(difluoromethyl)benzene (C100)
Figure img0187

[000261] Isolado como um sólido esbranquiçado (10,0 g, 34%): 1H RMN (400 MHz, CDCl3) δ 7,68 (d, J = 8,0 Hz, 1H), 7,43 (s, 1H), 7,38 (d, J = 8,4 Hz, 1H), 7,28 - 7,25 (m, 2H), 7,09 - 6,92 (m, 3H), 3,83 (s, 3H), 3,15 (q, J = 12,0 Hz, 2H); ESIMS m/z 376 ([M+H]+).trans-2-Flúor-4-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)-1-(difluoro- metil)benzeno (C101)

Figure img0188
[000261] Isolated as an off-white solid (10.0 g, 34%): 1H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H) ), 7.38 (d, J = 8.4 Hz, 1H), 7.28 - 7.25 (m, 2H), 7.09 - 6.92 (m, 3H), 3.83 (s, 3H), 3.15 (q, J = 12.0 Hz, 2H); ESIMS m/z 376 ([M+H]+).trans-2-Fluor-4-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)-1-(difluoromethyl)benzene (C101)
Figure img0188

[000262] Isolado como um líquido amarelo pálido (6,9 g, 58%): 1H RMN (400 MHz, CDCl3) δ 7,31 (t, J = 7,6 Hz, 1H), 7,27 (d, J = 9,2 Hz, 2H), 7,14 (d, J = 10,8 Hz, 1H), 7,04 - 6,76 (m, 4H), 3,83 (s, 3H), 3,16 (t, J = 8,8 Hz, 2H); 19F RMN (376 MHz, CDCl3) δ -114,14, - 114,32, -119,30.trans-1-(2,2-Dicloro-3-(4-metoxifenil)ciclopropil)-3-(difluorometil)ben- zeno (C102)

Figure img0189
[000262] Isolated as a pale yellow liquid (6.9 g, 58%): 1H NMR (400 MHz, CDCl 3 ) δ 7.31 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 9.2 Hz, 2H), 7.14 (d, J = 10.8 Hz, 1H), 7.04 - 6.76 (m, 4H), 3.83 (s, 3H), 3. 16 (t, J = 8.8 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ -114.14, - 114.32, -119.30.trans-1-(2,2-Dichloro-3-(4-methoxyphenyl)cyclopropyl)-3-(difluoromethyl) benzene (C102)
Figure img0189

[000263] Isolado como um sólido amarelo pálido (6,3 g, 95%): 1H RMN (400 MHz, CDCl3) δ 7,50 (br s, 4H), 7,29 (d, J = 8,8 Hz, 2H), 6,93 (d, J = 8,0 Hz, 2H), 6,67 (t, 1H), 3,83 (s, 3H), 3,19 (s, 2H); 19F RMN (376 MHz, CDCl3) δ -110,87, -111,02.trans-1-(2,2-Dicloro-3-(4-(difluorometil)fenil)ciclopropil)-4-metóxi- benzeno (C103)

Figure img0190
[000263] Isolated as a pale yellow solid (6.3 g, 95%): 1H NMR (400 MHz, CDCl 3 ) δ 7.50 (br s, 4H), 7.29 (d, J = 8.8 Hz , 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.67 (t, 1H), 3.83 (s, 3H), 3.19 (s, 2H); 19F NMR (376 MHz, CDCl3) δ -110.87, -111.02.trans-1-(2,2-Dichloro-3-(4-(difluoromethyl)phenyl)cyclopropyl)-4-methoxy-benzene (C103 )
Figure img0190

[000264] Isolado como um sólido branco (14 g, 69%): 1H RMN (400 MHz, CDCl3) δ 7,54 (d, J = 8,0 Hz, 2H), 7,46 (d, J = 8,0 Hz, 2H), 7,28 (t, J = 8,4 Hz, 2H), 6,93 (d, J = 8,0 Hz, 2H), 6,67 (t, J = 56,8 Hz, 1H), 3,83 (s, 3H), 3,18 (s, 2H).[000264] Isolated as a white solid (14 g, 69%): 1 H NMR (400 MHz, CDCl 3 ) δ 7.54 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8 .0 Hz, 2H), 7.28 (t, J = 8.4 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.67 (t, J = 56.8 Hz, 1H), 3.83 (s, 3H), 3.18 (s, 2H).

[000265] Os seguintes compostos foram preparados de maneirasemelhante ao procedimento descrito no Exemplo 13:trans-5-(3-(4-Bromo-3-clorofenil)-2,2-diclorociclopropano-1- carboxamido)-2-cloro-N-( 1 -cianociclopropil)benzamida (F66)

Figure img0191
[000265] The following compounds were prepared in a manner similar to the procedure described in Example 13: trans-5-(3-(4-Bromo-3-chlorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N -( 1 -cyanocyclopropyl)benzamide (F66)
Figure img0191

[000266] Isolado como um sólido esbranquiçado (0,209 g, 49%).trans-2-Cloro-5-(2,2-dicloro-3-(4-nitrofenil)ciclopropano-1-carboxamido)-N-(3,3-difluorociclobutil)benzamida (F69)

Figure img0192
[000266] Isolated as an off-white solid (0.209 g, 49%). trans-2-Chloro-5-(2,2-dichloro-3-(4-nitrophenyl)cyclopropane-1-carboxamido)-N-(3, 3-difluorocyclobutyl)benzamide (F69)
Figure img0192

[000267] Isolado como uma espuma amarela (0,095 g, 36%).trans-5-(2-Bromo-2-cloro-3-(3,5-diclorofenil)ciclopropano-1-carboxami- do)-2-cloro-N-(3,3-difluorociclobutil)benzamida (F71)

Figure img0193
[000267] Isolated as a yellow foam (0.095 g, 36%). trans-5-(2-Bromo-2-chloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-2-chloro -N-(3,3-difluorocyclobutyl)benzamide (F71)
Figure img0193

[000268] Isolado como um sólido branco (0,099 g, 57%).trans-5-(2-Bromo-2-cloro-3-(3,5-diclorofenil)ciclopropano-carboxamido)-2-cloro-N-( 1 -cianociclopropil)benxamida (F72)

Figure img0194
[000268] Isolated as a white solid (0.099 g, 57%). trans-5-(2-Bromo-2-chloro-3-(3,5-dichlorophenyl)cyclopropane-carboxamido)-2-chloro-N-( 1-cyanocyclopropyl)benxamide (F72)
Figure img0194

[000269] Isolado como uma espuma branca (85 g, 51%).trans-2-Cloro-5-(2,2-dicloro-3-(3-cloro-5-cianofenil)ciclopropano-1-car- boxamido)-N-(3,3-difluorociclobtil)benzamida (F77)

Figure img0195
[000269] Isolated as a white foam (85 g, 51%). trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-5-cyanophenyl)cyclopropane-1-carboxamido) -N-(3,3-difluorocyclobutyl)benzamide (F77)
Figure img0195

[000270] Isolado como um sólido branco (0,090 g, 48%).trans-2-Cloro-N-(1-cianociclopropil)-5-(2,2-dicloro-3-(3-cloro-5-cianofe-nil)ciclopropano-1-carboxamido)benzamida (F78)

Figure img0196
[000270] Isolated as a white solid (0.090 g, 48%). trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-(3-chloro-5-cyanophe-) nyl)cyclopropane-1-carboxamido)benzamide (F78)
Figure img0196

[000271] Isolado como um sólido branco (0,097 g, 54%).trans-2-Cloro-5-(2,2-dicloro-3-(3,4-diclorofenil)ciclopropano-1-carboxa- mido)-N-((R)-3-oxo-2-((2,2,2-trifluoroetil)isoxazolidin-4-il)benzamida (F79)

Figure img0197
[000271] Isolated as a white solid (0.097 g, 54%). trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N -((R)-3-oxo-2-((2,2,2-trifluoroethyl)isoxazolidin-4-yl)benzamide (F79)
Figure img0197

[000272] Isolado como um sólido amarelo claro (0,039 g, 25%).trans-2-Cloro-5-(2,2-dicloro-3-(3,4,5-triclorofenil)ciclopropano-1-carbo-xamido)-N-((R)-3-oxo-2-(2,2,2-trifluoroetil)isoxazolidin-4-il)benzamida (F80)

Figure img0198
[000272] Isolated as a pale yellow solid (0.039 g, 25%). trans-2-Chloro-5-(2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido )-N-((R)-3-oxo-2-(2,2,2-trifluoroethyl)isoxazolidin-4-yl)benzamide (F80)
Figure img0198

[000273] Isolado como um sólido amarelo claro (0,049 g, 33%). trans-5-(3-(4-Bromo-3,5-difluorofenil)-2,2-diclorociclopropano-1-carbo- xamido)-2-cloro-N-( 1 -cianociclopropil)benzamida (F82)

Figure img0199
[000273] Isolated as a pale yellow solid (0.049 g, 33%). trans-5-(3-(4-Bromo-3,5-difluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(1-cyanocyclopropyl)benzamide (F82)
Figure img0199

[000274] Isolado como uma espuma amarela (0,078 g, 57%).trans-5-(3-(4-Bromo-3-flúor-5-metoxifenil)-2,2-diclorociclopropano-1-carboxamido)-2-cloro-N-( 1 -cianociclopropil)benzamida (F83)

Figure img0200
[000274] Isolated as a yellow foam (0.078 g, 57%). trans-5-(3-(4-Bromo-3-fluoro-5-methoxyphenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2- chloro-N-(1-cyanocyclopropyl)benzamide (F83)
Figure img0200

[000275] Isolado como uma espuma amarela (0,042 g, 31%).trans-5-(3-(3-Bromo-5-flúor-4-metoxifenil)-2,2-diclorociclopropano-1-carboxamido)-2-cloro-N-( 1 -cianociclopropil)benzamida (F84)

Figure img0201
[000275] Isolated as a yellow foam (0.042 g, 31%). trans-5-(3-(3-Bromo-5-fluoro-4-methoxyphenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2- chloro-N-(1-cyanocyclopropyl)benzamide (F84)
Figure img0201

[000276] Isolado como uma espuma amarela (0,025 g, 18%).trans-2-Cloro-N-(1-cianociclopropil)-5-(2,2-dicloro-3-(3-cloro-5-fluoro-fenil)ciclopropano-1-carboxamido)benzamida (PF 1)

Figure img0202
[000276] Isolated as a yellow foam (0.025 g, 18%). trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-(3-chloro-5-fluoro-) phenyl)cyclopropane-1-carboxamido)benzamide (PF 1)
Figure img0202

[000277] Isolado como uma espuma branca (0,044 g, 31%). trans-2-Cloro-N-(1-cianociclopropil)-5-(2,2-dicloro-3-(4-cloro-3-fluorofenil)ciclopropano-1-carboxamido)benzamida (PF2)

Figure img0203
[000277] Isolated as a white foam (0.044 g, 31%). trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-(4-chloro-3-fluorophenyl)cyclopropane-1-carboxamido)benzamide (PF2)
Figure img0203

[000278] Isolado como um óleo incolor (0,028 g, 21%).trans-2-Cloro-N-(1-cianociclopropil)-5-(2,2-dicloro-3-(3-cloro-4-fluorofenil)ciclopropano-1-carboxamido)benzamida (PF3)

Figure img0204
[000278] Isolated as a colorless oil (0.028 g, 21%). trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl) cyclopropane-1-carboxamido)benzamide (PF3)
Figure img0204

[000279] Isolado como uma espuma branca (0,046 g, 33%).trans-5-(3-(3-Bromo-5-clorofenil)-2,2-diclorociclopropano-1-carboxa-mido)-2-cloro-N-( 1 -cianociclopropil)benzamida (PF4)

Figure img0205
[000279] Isolated as a white foam (0.046 g, 33%). trans-5-(3-(3-Bromo-5-chlorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro- N-(1-cyanocyclopropyl)benzamide (PF4)
Figure img0205

[000280] Isolado como uma espuma branca (0,008 g, 8%).trans-2-Cloro-5-(2,2-dicloro-3-(3-cloro-5-fluorofenil)ciclopropano-1-car-boxamido)-N-(3,3-difluorociclobutil)benzamida (PF5)

Figure img0206
[000280] Isolated as a white foam (0.008 g, 8%). trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-5-fluorophenyl)cyclopropane-1-carboxamido) -N-(3,3-difluorocyclobutyl)benzamide (PF5)
Figure img0206

[000281] Isolado como uma espuma branca (0,066 g, 45%).trans-2-Cloro-5-(2,2-dicloro-3-(4-cloro-3-fluorofenil)ciclopropano-1- carboxamido)-N-(3,3-difluorociclobutil)benzamida (PF6)

Figure img0207
[000281] Isolated as a white foam (0.066 g, 45%). trans-2-Chloro-5-(2,2-dichloro-3-(4-chloro-3-fluorophenyl)cyclopropane-1-carboxamido)-N -(3,3-difluorocyclobutyl)benzamide (PF6)
Figure img0207

[000282] Isolado como um óleo amarelo claro (0,102 g, 74%).trans-2-Cloro-5-(2,2-dicloro-3-(3-cloro-4-fluorofenil)ciclopropano-1-carboxamido)-N-(3,3-difluorociclobutil)benzamida (PF7)

Figure img0208
[000282] Isolated as a pale yellow oil (0.102 g, 74%). trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)- N-(3,3-difluorocyclobutyl)benzamide (PF7)
Figure img0208

[000283] Isolado como uma espuma branca (0,066 g, 45%).trans-5-(3-(3-Bromo-5-clorofenil)-2,2-diclorociclopropano-1-carbo-xamido)-2-cloro-N-(3,3-difluorociclobutil)benzamida (PF8)

Figure img0209
[000283] Isolated as a white foam (0.066 g, 45%). trans-5-(3-(3-Bromo-5-chlorophenyl)-2,2-dichlorocyclopropane-1-carbo-xamido)-2-chloro- N-(3,3-difluorocyclobutyl)benzamide (PF8)
Figure img0209

[000284] Isolado como uma espuma branca (0,044 g, 43%).trans-2-Cloro-5-(2,2-dicloro-3-(3,4,5-triclorofenil)ciclopropano-1-car-boxamido)-N-( 1, 1 -dioxidotetra-hidrotiofen-3-il)benzamida (PF 19)

Figure img0210
[000284] Isolated as a white foam (0.044 g, 43%). trans-2-Chloro-5-(2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido) -N-(1,1-dioxidotetrahydrothiophen-3-yl)benzamide (PF 19)
Figure img0210

[000285] Isolado como um pó branco (0,120 g, 63%).trans-2-Cloro-N-(1-cianociclopropil)-5-(2,2-dicloro-3-(3,5-dicloro-fenil) ciclopropano-1-carboxamido)-N-metilbenzamida (PF20)

Figure img0211
[000285] Isolated as a white powder (0.120 g, 63%). trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-(3,5-dichloro-phenyl) cyclopropane-1-carboxamido)-N-methylbenzamide (PF20)
Figure img0211

[000286] Isolado como uma espuma amarela (0,047 g, 33%).trans-2-Cloro-N-(1-cianociclopropil)-5-(2,2-dicloro-3-(3,4,5-tricloro-fenil)ciclopropano-1-carboxamido)-N-metilbenzamida (PF21)

Figure img0212
[000286] Isolated as a yellow foam (0.047 g, 33%). trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-(3,4,5-trichloro-) phenyl)cyclopropane-1-carboxamido)-N-methylbenzamide (PF21)
Figure img0212

[000287] Isolado como uma espuma amarela (0,072 g, 47%).trans-2-Cloro-N-(1-cianociclopropil)-5-(2,2-dicloro-3-(3,4-dicloro-fenil)ciclopropano-1-carboxamido)-N-metilbenzamida (PF22)

Figure img0213
[000287] Isolated as a yellow foam (0.072 g, 47%). trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-(3,4-dichloro-phenyl) cyclopropane-1-carboxamido)-N-methylbenzamide (PF22)
Figure img0213

[000288] Isolado como uma espuma amarela (0,068 g, 47%).trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropano-1-carbo-xamido)-N-(2,2-difluorociclopropil)benzamida (PF23)

Figure img0214
[000288] Isolated as a yellow foam (0.068 g, 47%). trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N -(2,2-difluorocyclopropyl)benzamide (PF23)
Figure img0214

[000289] Isolado como uma espuma branca (0,022 g, 38%).trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropano-1-carboxa-mido)-N-((R)-3-oxo-2-((2,2,2-trifluoroetil)isoxazolidin-4-il)benzamida (PF28)

Figure img0215
[000289] Isolated as a white foam (0.022 g, 38%). trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N -((R)-3-oxo-2-((2,2,2-trifluoroethyl)isoxazolidin-4-yl)benzamide (PF28)
Figure img0215

[000290] Isolado como um sólido amarelo claro (0,042 g, 27%).trans-2-Cloro-N-(1-cianopropil)-5-(2,2-dibromo-3-(3,5-diclorofenil)-ciclopropano-1-carboxamido)benzamida (PF30)

Figure img0216
[000290] Isolated as a pale yellow solid (0.042 g, 27%). trans-2-Chloro-N-(1-cyanopropyl)-5-(2,2-dibromo-3-(3,5-dichlorophenyl)- cyclopropane-1-carboxamido)benzamide (PF30)
Figure img0216

[000291] Isolado como uma espuma laranja clara (0,095 g, 67%).trans-2-Cloro-5-(2,2-dibromo-3-(3,5-diclorofenil)ciclopropano-1-carbo-xamido)-N-(3,3-difluorociclobutil)benzamida (PF31)

Figure img0217
[000291] Isolated as a light orange foam (0.095 g, 67%). trans-2-Chloro-5-(2,2-dibromo-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)- N-(3,3-difluorocyclobutyl)benzamide (PF31)
Figure img0217

[000292] Isolado como um vidro amarelo pálido (0,028 g, 27%).[000292] Isolated as a pale yellow glass (0.028 g, 27%).

[000293] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 14:trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropano-1-carboxa- mido)-N-(4-oxociclo-hexil)benzamida (F65)

Figure img0218
[000293] The following compounds were prepared in a manner similar to the procedure described in Example 14: trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxa- amide)-N-(4-oxocyclohexyl)benzamide (F65)
Figure img0218

[000294] Isolado como um pó branco (0,116 g, 38%).[000294] Isolated as a white powder (0.116 g, 38%).

[000295] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 15:2-Cloro-5-((1R,3R)-2,2-dicloro-3-(3,5-diclorofenil)ciclopropanocarboxa- mido)-N-(3,3-difluorociclobutil)benzamida (F73)

Figure img0219
[000295] The following compounds were prepared in a manner similar to the procedure described in Example 15: 2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarbox- amide)-N-(3,3-difluorocyclobutyl)benzamide (F73)
Figure img0219

[000296] Isolado como uma espuma branca (0,051 g, 29%).2-Cloro-5-((1S,3S)-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropano-1-car-boxamido)-N-((3,3-difluorociclobutil)benzamida (F74)

Figure img0220
[000296] Isolated as a white foam (0.051 g, 29%). 2-Chloro-5-((1S,3S)-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carton -boxamido)-N-((3,3-difluorocyclobutyl)benzamide (F74)
Figure img0220

[000297] Isolado como uma espuma branca (0,065 g, 37%).2-Cloro-N-( 1 -cianociclopropil)-5-((1 R,3R)-2,2-dicloro-3-(3,5-dicloro-fenil)ciclopropano-1-carboxamido)benzamida (F75)

Figure img0221
[000297] Isolated as a white foam (0.065 g, 37%). 2-Chloro-N-(1-cyanocyclopropyl)-5-((1R,3R)-2,2-dichloro-3-(3.5 -dichloro-phenyl)cyclopropane-1-carboxamido)benzamide (F75)
Figure img0221

[000298] Isolado como uma espuma dourada (0,025 g, 15%).2-Cloro-N-( 1 -cianociclopropil)-5-((1 S,3S)-2,2-dicloro-3-(3,5-dicloro-fenil)ciclopropanocarboxamido)benzamida (F76)

Figure img0222
[000298] Isolated as a golden foam (0.025 g, 15%). 2-Chloro-N-(1-cyanocyclopropyl)-5-((1S,3S)-2,2-dichloro-3-(3.5 -dichlorophenyl)cyclopropanecarboxamido)benzamide (F76)
Figure img0222

[000299] Isolado como uma espuma dourada (0,030 g, 18%).trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropano-1-carboxamido)-N-(2-oxopirrolidin-3-il)etil)benzamida (PF29)

Figure img0223
[000299] Isolated as a golden foam (0.030 g, 18%). trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-( 2-oxopyrrolidin-3-yl)ethyl)benzamide (PF29)
Figure img0223

[000300] Isolado como um sólido branco (0,102 g, 90%).[000300] Isolated as a white solid (0.102 g, 90%).

[000301] Os seguintes compostos foram preparados de maneira semelhante ao procedimento descrito no Exemplo 21:5-Amino-2-cloro-N-(1-cianociclopropil)-N-metilbenzamida (C104)

Figure img0224
[000301] The following compounds were prepared in a similar manner to the procedure described in Example 21:5-Amino-2-chloro-N-(1-cyanocyclopropyl)-N-methylbenzamide (C104)
Figure img0224

[000302] Isolado como um óleo amarelo (0,235 g, 100%): 1H RMN (400 MHz, CDCI3) δ 7,24 - 7,04 (m, 1H), 6,94 - 6,49 (m, 2H), 3,82 (s, 2H), 2,93 (s, 3H), 2,14 (s, 2H), 1,45 (s, 2H); IR (película fina) 3360, 2236, 1654, 1477, 1374 cm-1; ESIMS m/z 250 ([M+H]+).5-Amino-2-cloro-N-(2,2-difluorociclopropil)benzamida (C105)

Figure img0225
[000302] Isolated as a yellow oil (0.235 g, 100%): 1H NMR (400 MHz, CDCl 3 ) δ 7.24 - 7.04 (m, 1H), 6.94 - 6.49 (m, 2H) , 3.82 (s, 2H), 2.93 (s, 3H), 2.14 (s, 2H), 1.45 (s, 2H); IR (thin film) 3360, 2236, 1654, 1477, 1374 cm-1; ESIMS m/z 250 ([M+H]+).5-Amino-2-chloro-N-(2,2-difluorocyclopropyl)benzamide (C105)
Figure img0225

[000303] Isolado como um sólido amarelo (0,027 g, 56%): 1H RMN (300 MHz, CD3OD) δ 7,13 - 7,08 (m, 1H), 6,73 - 6,68 (m, 2H), 3,43 (tdd, J = 10,2, 6,1, 1,8 Hz, 1H), 1,87 (dddd, J = 13,3, 10,3, 8,9, 6,4 Hz, 1H), 1,52 (dddd, J = 14,5, 8,9, 6,2, 4,7 Hz, 1H); IR (película fina) 3300, 1646, 1473 cm-1; ESIMS m/z 247 ([M+H]+).[000303] Isolated as a yellow solid (0.027 g, 56%): 1H NMR (300 MHz, CD3OD) δ 7.13 - 7.08 (m, 1H), 6.73 - 6.68 (m, 2H) , 3.43 (tdd, J = 10.2, 6.1, 1.8 Hz, 1H), 1.87 (dddd, J = 13.3, 10.3, 8.9, 6.4 Hz, 1H), 1.52 (dddd, J = 14.5, 8.9, 6.2, 4.7 Hz, 1H); IR (thin film) 3300, 1646, 1473 cm-1; ESIMS m/z 247 ([M+H]+).

[000304] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 24: (R)-5-Amino-2-cloro-N-(3-oxo-2-((2,2,2-trifluoroetil)isoxazolidin-4- il)benzamida (C106)

Figure img0226
[000304] The following compounds were prepared in a similar manner to the procedure described in Example 24: (R)-5-Amino-2-chloro-N-(3-oxo-2-((2,2,2-trifluoroethyl) )isoxazolidin-4-yl)benzamide (C106)
Figure img0226

[000305] Isolado como um óleo amarelo (0,320 g, 75%): 1H RMN (400 MHz, DMSO-d6) δ 8,94 (d, J = 8,2 Hz, 1H), 7,08 (d, J = 8,4 Hz, 1H), 6,68 - 6,53 (m, 2H), 5,46 (s, 2H), 5,09 - 4,95 (m, 1H), 4,65 (t, J = 8,6 Hz, 1H), 4,46 - 4,25 (m, 2H), 4,19 - 4,06 (m, 1H); 19F RMN (376 MHz, DMSO-d6) δ -69,11; ESIMS m/z 338 ([M+H]+).[000305] Isolated as a yellow oil (0.320 g, 75%): 1H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.68 - 6.53 (m, 2H), 5.46 (s, 2H), 5.09 - 4.95 (m, 1H), 4.65 (t, J = 8.6 Hz, 1H), 4.46 - 4.25 (m, 2H), 4.19 - 4.06 (m, 1H); 19F NMR (376 MHz, DMSO-d6) δ -69.11; ESIMS m/z 338 ([M+H]+).

[000306] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 25: 5-Amino-2-cloro-N-( 1, 1 -dioxidotetra-hidrotiofen-3-il)benzamida (C107)

Figure img0227
[000306] The following compounds were prepared in a manner similar to the procedure described in Example 25: 5-Amino-2-chloro-N-(1,1-dioxidotetrahydrothiophen-3-yl)benzamide (C107)
Figure img0227

[000307] Isolado como pó rosa (0,093 g, 36%): pf 160 - 163°C; 1H RMN (400 MHz, DMSO-d6) δ 8,76 (d, J = 7 Hz, 1H), 7,07 (d, J = 8 Hz, 1H), 6,63 - 6,55 (m, 2H), 5,42 (br s, 2H), 4,60 (m, 1H), 3,49 (dd, J = 13,5, 7,8 Hz, 1H), 3,31 (m, 1H), 3,18 (m, 1H), 2,97 (dd, J = 13, 7,2 Hz, 1H), 2,41 (m, 1H), 2,12 (m, 1H); IR (película fina) 3458 (w), 3370 (w), 3257 (w), 1646 (m), 1535 (m), 1479 (w) cm-1; ESIMS m/z 289 ([M+H]+).[000307] Isolated as pink powder (0.093 g, 36%): mp 160 - 163°C; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 7 Hz, 1H), 7.07 (d, J = 8 Hz, 1H), 6.63 - 6.55 (m, 2H) ), 5.42 (br s, 2H), 4.60 (m, 1H), 3.49 (dd, J = 13.5, 7.8 Hz, 1H), 3.31 (m, 1H), 3.18 (m, 1H), 2.97 (dd, J = 13, 7.2 Hz, 1H), 2.41 (m, 1H), 2.12 (m, 1H); IR (thin film) 3458 (w), 3370 (w), 3257 (w), 1646 (m), 1535 (m), 1479 (w) cm-1; ESIMS m/z 289 ([M+H]+).

[000308] Os seguintes compostos foram preparados de maneira semelhante ao procedimento descrito no Exemplo 26: (R)-2-Cloro-5-nitro-N-(3-oxo-2-((2,2,2-trifluoroetil)isoxazolidin-4- il)benzamida (C108)

Figure img0228
[000308] The following compounds were prepared in a similar manner to the procedure described in Example 26: (R)-2-Chloro-5-nitro-N-(3-oxo-2-((2,2,2-trifluoroethyl)isoxazolidin -4-yl)benzamide (C108)
Figure img0228

[000309] Isolado como um óleo laranja (0,355 g, 70%): 1H RMN (300 MHz, DMSO-d6) δ 9,44 (d, J = 7,7 Hz, 1H), 8,35 - 8,29 (m, 2H), 7,92 - 7,81 (m, 1H), 5,15 - 5,02 (m, 1H), 4,72 (t, J = 8,6 Hz, 1H), 4,48 - 4,35 (m, 2H), 4,22 (t, J = 8,6 Hz, 1H); 19F RMN (376 MHz, DMSO-d6) δ -69,11; ESIMS m/z 368 ([M+H]+).[000309] Isolated as an orange oil (0.355 g, 70%): 1H NMR (300 MHz, DMSO-d6) δ 9.44 (d, J = 7.7 Hz, 1H), 8.35 - 8.29 (m, 2H), 7.92 - 7.81 (m, 1H), 5.15 - 5.02 (m, 1H), 4.72 (t, J = 8.6 Hz, 1H), 4, 48 - 4.35 (m, 2H), 4.22 (t, J = 8.6 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ -69.11; ESIMS m/z 368 ([M+H]+).

[000310] Os seguintes compostos foram preparados de maneira seme-lhante ao procedimento descrito no Exemplo 28: 2-Cloro-N-(1-cianociclopropil)-N-metil-5-nitrobenzamida (C109)

Figure img0229
[000310] The following compounds were prepared in a manner similar to the procedure described in Example 28: 2-Chloro-N-(1-cyanocyclopropyl)-N-methyl-5-nitrobenzamide (C109)
Figure img0229

[000311] Isolado como um sólido branco (0,280 g, 87%): 1H RMN (400 MHz, DMSO-d6) δ 8,40 (d, J = 2,8 Hz, 1H), 8,30 (dd, J = 8,8, 2,8 Hz, 1H), 7,87 (d, J = 8,8 Hz, 1H), 2,84 (s, 3H), 1,73 - 1,38 (m, 4H); ESIMS m/z 280 ([M+H]+).Exemplo 29: Preparação de trans-2-cloro-N-(1-cianociclopropil)-5-(2,2- dicloro-3-(3-cloro-4-vinilfenil)ciclopropano-1-carboxamido)benzamida (F67)

Figure img0230
[000311] Isolated as a white solid (0.280 g, 87%): 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 2.8 Hz, 1H), 8.30 (dd, J = 8.8, 2.8 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 2.84 (s, 3H), 1.73 - 1.38 (m, 4H) ; ESIMS m/z 280 ([M+H]+).Example 29: Preparation of trans-2-chloro-N-(1-cyanocyclopropyl)-5-(2,2-dichloro-3-(3-chloro-4) -vinylphenyl)cyclopropane-1-carboxamido)benzamide (F67)
Figure img0230

[000312] Uma solução de trans-5-(3-(4-bromo-3-clorofenil)-2,2-diclorociclopropano-1-carboxamido)-2-cloro-N-(1-cianociclopropil)benzamida (F66) (0,1 g, 0,178 mmol) diclorobis(trife- nilfosfina)paládio(II) (0,025 g, 0,036 mmol) e tributil(vinil)estanana (0,156 mL, 0,169 mmol) em 1,4-dioxano (1 mL) foi vedada em uma atmosfera de nitrogênio e aquecida até 90°C por 1 hora via irradiação por micro-ondas. A reação foi diluída com acetato de etila e, em seguida, foi filtrada através de 15 g de 10:1 de gel de sílica:carbonato de potássio, lavando com ace-tato de etila. A solução foi concentrada e o material bruto resultante foi carregado em um cartucho pré-carregado contendo 5 g de 5:1 de gel de sílica:fluoreto de potássio. A purificação por cromatografia flash em coluna usando 0-35% de acetato de etila/hexanos como eluente gerou o composto do título como uma espuma amarela clara (0,091 g, 61%).Exemplo 30: Preparação de trans-5-(3-(4-aminofenil)-2,2-dicloro-propano- 1-carboxamido)-2-cloro-N-(3,3-difluorociclobutil)benzamida (F70)

Figure img0231
[000312] A solution of trans-5-(3-(4-bromo-3-chlorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(1-cyanocyclopropyl)benzamide (F66) ( 0.1 g, 0.178 mmol) dichlorobis(triphenylphosphine)palladium(II) (0.025 g, 0.036 mmol) and tributyl(vinyl)stannane (0.156 mL, 0.169 mmol) in 1,4-dioxane (1 mL) was sealed in a nitrogen atmosphere and heated to 90°C for 1 hour via microwave irradiation. The reaction was diluted with ethyl acetate and then filtered through 15 g of 10:1 silica gel:potassium carbonate, washing with ethyl acetate. The solution was concentrated and the resulting crude material was loaded into a preloaded cartridge containing 5 g of 5:1 silica gel:potassium fluoride. Purification by flash column chromatography using 0-35% ethyl acetate/hexanes as eluent gave the title compound as a light yellow foam (0.091 g, 61%). Example 30: Preparation of trans-5-(3- (4-aminophenyl)-2,2-dichloro-propane-1-carboxamido)-2-chloro-N-(3,3-difluorocyclobutyl)benzamide (F70)
Figure img0231

[000313] A uma pasta líquida de trans-2-cloro-5-(2,2-dicloro-3-(4- nitrofenil)ciclopropano-1-carboxamido)-N-(3,3-difluorociclobutil)benzamida (F69) (60 mg, 0,116 mmol) em matanol (1,0 mL) e água (0,36 mL) foi adi-cionado pó de ferro (32,3 mg, 0,578 mmol) e cloreto de amônio (19 mg, 0,347 mmol). A pasta foi agitada a 55°C por 3 horas. A mistura de reação foi filtrada através de uma almofada de Celite® lavando com acetato de etila e o filtrado foi concentrado. A purificação por cromatografia flash em coluna usando 0-100% de acetato de etila/hexanos como eluente forneceu o composto do título como uma espuma laranja (0,049 g, 82%).Exemplo 31: Preparação de trans-2-cloro-5-(2,2-dicloro-3-(3,5-dicloro- fenil)-3-metilciclopropano-1-carboxamido)-N-(3,3-difluorociclobutil)- benzamida (F61)

Figure img0232
[000313] To a slurry of trans-2-chloro-5-(2,2-dichloro-3-(4-nitrophenyl)cyclopropane-1-carboxamido)-N-(3,3-difluorocyclobutyl)benzamide (F69) (60 mg, 0.116 mmol) in methanol (1.0 mL) and water (0.36 mL) was added iron powder (32.3 mg, 0.578 mmol) and ammonium chloride (19 mg, 0.347 mmol) . The slurry was stirred at 55°C for 3 hours. The reaction mixture was filtered through a pad of Celite® washing with ethyl acetate and the filtrate was concentrated. Purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent provided the title compound as an orange foam (0.049 g, 82%). Example 31: Preparation of trans-2-chloro-5- (2,2-dichloro-3-(3,5-dichloro-phenyl)-3-methylcyclopropane-1-carboxamido)-N-(3,3-difluorocyclobutyl)-benzamide (F61)
Figure img0232

[000314] A uma solução de 5-amino-2-cloro-N-(3,3-difluorociclobutil) benzamida(C71) (0,0623 g, 0,239 mmol) e ácido trans-2,2-dicloro-3- (3,5-diclorofenil)-3-metilciclopropanocarboxílico (C2) (0,075 g, 0,239 mmol) em acetato de etila (3 mL) foram adicionados piridina (0,058 mL, 0,717 mmol) seguido de 2,4,6-tripropil-1,3,5,2,4,6-trioxatrifosfori- nano-2,4,6-trióxido (T3P®, solução a 50% em acetato de etila, 304 mg, 0,478 mmol), e a solução amarela clara resultante foi agitada à temperatura ambiente por aproximadamente 14 horas. A solução foi concentrada sob um fluxo de nitrogênio e purificada por cromatografia flash em coluna de sílica gel com uma fase móvel de hexanos/acetato de etila. As frações puras foram combinadas e concentradas em vácuo em um evaporador rotativo para fornecer o composto do título como uma espuma branca (0,080 g, 59%).[000314] To a solution of 5-amino-2-chloro-N-(3,3-difluorocyclobutyl)benzamide (C71) (0.0623 g, 0.239 mmol) and trans-2,2-dichloro-3-( acid) 3,5-dichlorophenyl)-3-methylcyclopropanecarboxylic (C2) (0.075 g, 0.239 mmol) in ethyl acetate (3 mL) was added pyridine (0.058 mL, 0.717 mmol) followed by 2,4,6-tripropyl-1. 3,5,2,4,6-trioxatriphosphorine-2,4,6-trioxide (T3P®, 50% solution in ethyl acetate, 304 mg, 0.478 mmol), and the resulting light yellow solution was stirred at at room temperature for approximately 14 hours. The solution was concentrated under a stream of nitrogen and purified by flash chromatography on a silica gel column with a mobile phase of hexanes/ethyl acetate. The pure fractions were combined and concentrated in vacuo on a rotary evaporator to provide the title compound as a white foam (0.080g, 59%).

[000315] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 31: cis-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)-3-metilciclopropano-1-car- boxamido)-N-((3,3-difluorociclobutil)benzamida (F62)

Figure img0233
[000315] The following compounds were prepared in a manner similar to the procedure described in Example 31: cis-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)-3-methylcyclopropane-1 -carboxamido)-N-((3,3-difluorocyclobutyl)benzamide (F62)
Figure img0233

[000316] Isolado como um sólido branco (0,030 g, 38%).2-Cloro-N-( 1 -cianociclopropil)-5-((1 R,3R)-(2,2-dicloro-3-(3,4,5-tricloro- fenil)ciclopropano-1-carboxamido)benzamida (F63)

Figure img0234
[000316] Isolated as a white solid (0.030 g, 38%). 2-Chloro-N-(1-cyanocyclopropyl)-5-((1R,3R)-(2,2-dichloro-3-(3, 4,5-trichlorophenyl)cyclopropane-1-carboxamido)benzamide (F63)
Figure img0234

[000317] Isolado como uma espuma branca (0,083 g, 64%).2-Cloro-N-( 1 -cianociclopropil)-5-((1 S,3S)-(2,2-dicloro-3-(3,4,5-tricloro- fenil)ciclopropano-1-carboxamido)benzamida (F64)

Figure img0235
[000317] Isolated as a white foam (0.083 g, 64%). 2-Chloro-N-(1-cyanocyclopropyl)-5-((1S,3S)-(2,2-dichloro-3-(3, 4,5-trichlorophenyl)cyclopropane-1-carboxamido)benzamide (F64)
Figure img0235

[000318] Isolado como uma espuma branca (0,082 g, 63%).trans-2-Cloro-N-(1-cianociclopropil-5-(2,2-dicloro-3-(3-cloro-5-difluoro-metil)fenil)ciclopropano-1-carboxamido)benzamida (F85)

Figure img0236
[000318] Isolated as a white foam (0.082 g, 63%). trans-2-Chloro-N-(1-cyanocyclopropyl-5-(2,2-dichloro-3-(3-chloro-5-difluoro-methyl) )phenyl)cyclopropane-1-carboxamido)benzamide (F85)
Figure img0236

[000319] Isolado como um óleo incolor (0,080 g, 72%).trans-2-Cloro-N-(1-cianociclopropil-5-(2,2-dicloro-3-(4-cloro-3-(difluoro-metil)fenil)ciclopropano-1-carboxamido)benzamida (F86)

Figure img0237
[000319] Isolated as a colorless oil (0.080 g, 72%). trans-2-Chloro-N-(1-cyanocyclopropyl-5-(2,2-dichloro-3-(4-chloro-3-(difluoro-)) methyl)phenyl)cyclopropane-1-carboxamido)benzamide (F86)
Figure img0237

[000320] Isolado como um óleo incolor (0,069 g, 62%).trans-2-Cloro-N-(1-cianociclopropil-5-(2,2-dicloro-3-(3-(difluoro-metil)-5-fluorofenil)ciclopropano-1-carboxamido)benzamida (F87)

Figure img0238
[000320] Isolated as a colorless oil (0.069 g, 62%). trans-2-Chloro-N-(1-cyanocyclopropyl-5-(2,2-dichloro-3-(3-(difluoro-methyl)-5) -fluorophenyl)cyclopropane-1-carboxamido)benzamide (F87)
Figure img0238

[000321] Isolado como um óleo incolor (0,084 g, 77%). trans-2-Cloro-N-(1-cianociclopropil-5-(2,2-dicloro-3-(3-(difluoro-metil)-4-fluorofenil)ciclopropano-1-carboxamido)benzamida (F88)

Figure img0239
[000321] Isolated as a colorless oil (0.084 g, 77%). trans-2-Chloro-N-(1-cyanocyclopropyl-5-(2,2-dichloro-3-(3-(difluoro-methyl)-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide (F88)
Figure img0239

[000322] Isolado como um óleo incolor (0,018 g, 16%).trans-2-Cloro-N-(1-cianociclopropil-5-(2,2-dicloro-3-(3-cloro-4-(difluorometil)fenil)ciclopropano-1-carboxamido)benzamida (F89)

Figure img0240
[000322] Isolated as a colorless oil (0.018 g, 16%). trans-2-Chloro-N-(1-cyanocyclopropyl-5-(2,2-dichloro-3-(3-chloro-4-(difluoromethyl)) phenyl)cyclopropane-1-carboxamido)benzamide (F89)
Figure img0240

[000323] Isolado como um óleo incolor (0,076 g, 68%).trans-2-Cloro-N-(1-cianociclopropil-5-(2,2-dicloro-3-(4-(difluorometil)-3-fluorofenil)ciclopropano-1-carboxamido)benzamida (F90)

Figure img0241
[000323] Isolated as a colorless oil (0.076 g, 68%). trans-2-Chloro-N-(1-cyanocyclopropyl-5-(2,2-dichloro-3-(4-(difluoromethyl))-3-fluorophenyl )cyclopropane-1-carboxamido)benzamide (F90)
Figure img0241

[000324] Isolado como um óleo incolor (0,041 g, 38%).trans-2-Cloro-N-( 1 -cianociclopropil-5-(2,2-dicloro-3-(3-(difluorometil)fenil)ciclopropano-1-carboxamido)benzamida (F91)

Figure img0242
[000324] Isolated as a colorless oil (0.041 g, 38%). trans-2-Chloro-N-(1-cyanocyclopropyl-5-(2,2-dichloro-3-(3-(difluoromethyl)phenyl)cyclopropane- 1-carboxamido)benzamide (F91)
Figure img0242

[000325] Isolado como um óleo incolor (0,072 g, 69%).trans-2-Cloro-N-(1-cianociclopropil-5-(2,2-dicloro-3-(4-(difluorometil)-fenil)ciclopropano-1-carboxamido)benzamida (F92)

Figure img0243
[000325] Isolated as a colorless oil (0.072 g, 69%). trans-2-Chloro-N-(1-cyanocyclopropyl-5-(2,2-dichloro-3-(4-(difluoromethyl)-phenyl)-cyclopropane -1-carboxamido)benzamide (F92)
Figure img0243

[000326] Isolado como um óleo incolor (0,093 g, 89%).Exemplo 32: Preparação de trans-2-cloro-5-(2,2-dicloro-3-(3,5-dicloro-fenil)ciclopropano-1-carboxamido)-N-(3-oxociclobutil)benzamida (F68)

Figure img0244
[000326] Isolated as a colorless oil (0.093 g, 89%).Example 32: Preparation of trans-2-chloro-5-(2,2-dichloro-3-(3,5-dichloro-phenyl)cyclopropane-1 -carboxamido)-N-(3-oxocyclobutyl)benzamide (F68)
Figure img0244

[000327] A uma mistura de ácido 2-cloro-5-(2,2-dicloro-3-(3,5- diclorofenil)ciclopropano-carboxamido)benzoico (C67) (0,150 g, 0,33 mmol) e cloridrato de 3-aminociclobutan-1-ona (0,055 g, 0,36 mmol) em acetato de etila (3,3 mL) agitado em 23°C foram adicionados pi- ridina (0,080 mL, 0,99 mmol), seguida de 50% de solução de 2,4,6- tripropil-1,3,5,2,4,6-trioxatrifosfinana 2,4,6-trióxido (T3P®) em acetato de etila (300 μL, 0,50 mmol). A mistura de reação foi aquecida até 50°C e agitada por 18 horas. A mistura de reação foi concentrada e o resíduo foi purificado por cromatografia flash em coluna de fase reversa usando 5-100% de acetonitrila/água como eluente para fornecer o produto do título como um pó branco (0,031 g, 18%).[000327] To a mixture of 2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-carboxamido)benzoic acid (C67) (0.150 g, 0.33 mmol) and hydrochloride 3-aminocyclobutan-1-one (0.055 g, 0.36 mmol) in ethyl acetate (3.3 mL) stirred at 23°C was added pyridine (0.080 mL, 0.99 mmol), followed by 50% of solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan 2,4,6-trioxide (T3P®) in ethyl acetate (300 µL, 0.50 mmol). The reaction mixture was heated to 50°C and stirred for 18 hours. The reaction mixture was concentrated and the residue was purified by reverse phase flash column chromatography using 5-100% acetonitrile/water as eluent to furnish the title product as a white powder (0.031 g, 18%).

[000328] Os seguintes compostos foram preparados de maneira semelhante ao procedimento descrito no Exemplo 32: trans-2-Cloro-5-(2,2-dicloro-3-(3-cloro-4-fluorofenil)ciclopropano-1- carboxamido)-N-(4-oxociclo-hexil)benzamida (F81)

Figure img0245
[000328] The following compounds were prepared in a similar manner to the procedure described in Example 32: trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido) -N-(4-oxocyclohexyl)benzamide (F81)
Figure img0245

[000329] Isolado como uma película branca (0,106 g, 22%).Exemplo 33: Preparação de trans-2-Cloro-N-(1-(ciclopropanocarbonil)- azetidin-3-il-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropano-1-carboxa- mido) benzamida (PF9)

Figure img0246
[000329] Isolated as a white film (0.106 g, 22%). Example 33: Preparation of trans-2-Chloro-N-(1-(cyclopropanecarbonyl)-azetidin-3-yl-5-(2,2-dichloro) -3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide) benzamide (PF9)
Figure img0246

[000330] O ácido trifluoroacético (0,13 mL, 1,7 mmol) foi adicionado a uma mistura agitada de trans-terc-butil 3-(2-cloro-5-(2,2-dicloro-3- (3,5-diclorofenil)ciclopropanocarboxamido)-benzamido)azetidina-1-car- boxilato (F54) (0,10 g, 0,17 mmol) em diclorometano (1,6 mL) em 23°C. A solução incolor homogênea resultante foi agitada em 23°C por 4 horas. A mistura de reação foi concentrada e o resíduo foi reconstituído em diclorometano (1,6 mL). Trietilamina (0,050 mL, 0,25 mmol), cloreto de ciclopropanocarbonil (0,018 mL, 0,20 mmol) e 4-dimetila- minopiridina (0,024 g, 0,20 mmol) foram adicionados sequencialmente. A solução incolor homogênea resultante foi agitada em 23°C por 72 horas. A mistura de reação foi concentrada e o resíduo foi purificado por cromatografia flash em coluna de fase reversa usando 5-100% de acetonitrila/água como eluente para fornecer o produto do título como uma espuma branca (0,070 g, 74%).[000330] Trifluoroacetic acid (0.13 mL, 1.7 mmol) was added to a stirred mixture of trans-tert-butyl 3-(2-chloro-5-(2,2-dichloro-3-3, 5-dichlorophenyl)cyclopropanecarboxamido)-benzamido)azetidine-1-carboxylic acid (F54) (0.10 g, 0.17 mmol) in dichloromethane (1.6 mL) at 23°C. The resulting homogeneous colorless solution was stirred at 23°C for 4 hours. The reaction mixture was concentrated and the residue was reconstituted in dichloromethane (1.6 ml). Triethylamine (0.050 mL, 0.25 mmol), cyclopropanecarbonyl chloride (0.018 mL, 0.20 mmol) and 4-dimethylaminopyridine (0.024 g, 0.20 mmol) were added sequentially. The resulting homogeneous colorless solution was stirred at 23°C for 72 hours. The reaction mixture was concentrated and the residue was purified by reverse phase flash column chromatography using 5-100% acetonitrile/water as eluent to furnish the title product as a white foam (0.070 g, 74%).

[000331] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 33: trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropano-1-carboxa-mido)-N-( 1 -(3,3,3-trifluoropropanoil)azetidin-3-il)benzamida (PF 12)

Figure img0247
[000331] The following compounds were prepared in a manner similar to the procedure described in Example 33: trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxa- amide)-N-(1-(3,3,3-trifluoropropanoyl)azetidin-3-yl)benzamide (PF 12)
Figure img0247

[000332] Isolado como uma espuma marrom (0,026 g, 25%):trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropano-1-carboxa-mido)-N-( 1 -(2-(metoxiacetil)azetidin-3-il)benzamida (PF 14)

Figure img0248
[000332] Isolated as a brown foam (0.026 g, 25%): trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N -( 1 -(2-(methoxyacetyl)azetidin-3-yl)benzamide (PF 14)
Figure img0248

[000333] Isolado como uma espuma amarela clara (0,062 g, 65%):Exemplo 34: Preparação de trans-2-Cloro-5-(2,2-dicloro-3-(3,5-dicloro-fenil)ciclopropanocarboxamido)-N-(1-metilciclopropil)benzamida(PF32)

Figure img0249
[000333] Isolated as a light yellow foam (0.062 g, 65%): Example 34: Preparation of trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichloro-phenyl)cyclopropanecarboxamido) -N-(1-methylcyclopropyl)benzamide(PF32)
Figure img0249

[000334] A uma solução de ácido trans-2-cloro-5-(2,2-dicloro-3-(3,5- diclorofenil)ciclo-propanocarboxamido)benzoico (C67) (0,100 g, 0,220 mmol) em diclorometano (2,205 mL) a 0°C foi adicionada 1 gota de N,N-dimetilformamida e cloreto de oxalila (0,029 mL, 0,331 mmol) gota a gota. O banho frio foi removido, e a reação foi agitada em temperatura ambiente por 1 hora. A mistura de reação foi resfriada até 0°C, e N- metilmorfolina (0,073 mL, 0,661 mmol) e cloridrato de 1-metilciclopro- panamina (0,047 g, 0,441 mmol) foram adicionados sequencialmente. A mistura de reação foi agitada em temperatura ambiente por 3 dias. A mistura de reação foi introduzida em Celite® e foi purificada por croma- tografia (0-100% de acetato de etila em hexanos) para gerar trans-2- cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropanocarboxamido)-N-(1- metilciclopropil)benzamida (0,088 g, 75%) como um óleo transparente.[000334] To a solution of trans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido)benzoic acid (C67) (0.100 g, 0.220 mmol) in dichloromethane ( 2.205 ml) at 0°C was added 1 drop of N,N-dimethylformamide and oxalyl chloride (0.029 ml, 0.331 mmol) dropwise. The cold bath was removed, and the reaction was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, and N-methylmorpholine (0.073 mL, 0.661 mmol) and 1-methylcyclopropanamine hydrochloride (0.047 g, 0.441 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was introduced into Celite® and purified by chromatography (0-100% ethyl acetate in hexanes) to give trans-2-chloro-5-(2,2-dichloro-3-(3, 5-dichlorophenyl)cyclopropanecarboxamido)-N-(1-methylcyclopropyl)benzamide (0.088 g, 75%) as a clear oil.

[000335] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 34:trans-Metil 1-(2-cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropano-car- boxamido)benzamido)ciclopentanocarboxilato (PF33)

Figure img0250
[000335] The following compounds were prepared in a manner similar to the procedure described in Example 34: trans-Methyl 1-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-) carboxamido)benzamido)cyclopentanecarboxylate (PF33)
Figure img0250

[000336] Isolado como um sólido branco (0,074 g, 55%).trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropanocarboxami-do)-N-(2-oxo-oxazolidin-3-il)benzamida (PF34)

Figure img0251
[000336] Isolated as a white solid (0.074 g, 55%). trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido)-N-(2- oxo-oxazolidin-3-yl)benzamide (PF34)
Figure img0251

[000337] Isolado como um sólido branco (0,027 g, 22%).trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropano-1-carboxa-mido)-N-(2-oxotetra-hidrotiofen-3-il)benzamida (PF36)

Figure img0252
[000337] Isolated as a white solid (0.027 g, 22%). trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N -(2-oxotetrahydrothiophen-3-yl)benzamide (PF36)
Figure img0252

[000338] Isolado como um sólido branco (0,064 g, 50%).trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropano-1-carboxa- mido)-N-(2-oxotetra-hidrofuran-3-il)benzamida (PF37)

Figure img0253
[000338] Isolated as a white solid (0.064 g, 50%). trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N -(2-oxotetrahydrofuran-3-yl)benzamide (PF37)
Figure img0253

[000339] Isolado como um sólido branco (0,045 g, 36%).trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropano-1-carboxa-mido)-N-(5-(morfolinometil)-2-oxo-oxazolidin-3-il)benzamida (PF41)

Figure img0254
[000339] Isolated as a white solid (0.045 g, 36%). trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N -(5-(morpholinomethyl)-2-oxo-oxazolidin-3-yl)benzamide (PF41)
Figure img0254

[000340] Isolado como um sólido branco (0,059 g, 36%).trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropano-1-carboxa-mido)-N-( 1 -(2,2,2-trifluoroetil)carbamoil)ciclopropil)benzamida (PF42)

Figure img0255
[000340] Isolated as a white solid (0.059 g, 36%). trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N -( 1 -(2,2,2-trifluoroethyl)carbamoyl)cyclopropyl)benzamide (PF42)
Figure img0255

[000341] Isolado como um sólido branco (0,091 g, 64%).trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropano-1-carbo-xamido)-N-( 1 -(etilcarbamoil)ciclopropil)benzamida (PF43)

Figure img0256
[000341] Isolated as a white solid (0.091 g, 64%). trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamid)-N -( 1 -(ethylcarbamoyl)cyclopropyl)benzamide (PF43)
Figure img0256

[000342] Isolado como um sólido branco (0,085 g, 62%).trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropano-1-carboxa- mido)-N-(2-oxo-3-(2,2,2-trifluoroetil)imidazolidin-1-il)benzamida (PF44)

Figure img0257
[000342] Isolated as a white solid (0.085 g, 62%). trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N -(2-oxo-3-(2,2,2-trifluoroethyl)imidazolidin-1-yl)benzamide (PF44)
Figure img0257

[000343] Isolado como um sólido branco (0,042 g, 51%).trans-2-Cloro-5-(2,2-dicloro-3-(3,5-diclorofenil)ciclopropano-1-carboxa-mido)-N-((R)-2-etil-3-oxoisoxazolidin-4-il)benzamida (PF45)

Figure img0258
[000343] Isolated as a white solid (0.042 g, 51%). trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N -((R)-2-ethyl-3-oxoisoxazolidin-4-yl)benzamide (PF45)
Figure img0258

[000344] Isolado como um sólido branco (0,060 g, 63%).Exemplo 35: Preparação detrans-2-cloro-5-(2,2-dicloro-3-(3,4,5-tricloro-fenil)ciclopropano-1-carboxamido)-N-( 1 -oxidotetra-hidrotiofen-3-il)-ben-zamida (PF18)

Figure img0259
[000344] Isolated as a white solid (0.060 g, 63%).Example 35: Preparation of trans-2-chloro-5-(2,2-dichloro-3-(3,4,5-trichloro-phenyl)cyclopropane- 1-carboxamido)-N-(1-oxidotetrahydrothiophen-3-yl)-benzamide (PF18)
Figure img0259

[000345] A uma solução de trans-2-cloro-5-(2,2-dicloro-3-(3,4,5,-tri- clorofenil)ciclo-propanocarboxamido)-N-(tetra-hidrotiofen-3-il)benzami- da (F8) (0,150 g, 0,27 mmol) em ácido acético glacial (2,6 mL) foi adicionado tetra-hidrato de perborato de sódio (0,0630 g, 0,282 mmol). A reação foi aquecida até 60°C e agitada por 4 horas. Adicionou-se bicarbonato de sódio aquoso saturado e a mistura foi extraída com diclo- rometano. As fases orgânicas combinadas foram secas sobre sulfato de magnésio, filtradas e concentradas. O resíduo foi umedecido em hexano e filtrado a vácuo para fornecer o composto do título como um pó marrom amarelado (0,068 g, 44%).Exemplo 36: Preparação de ácido trans-2,2-dicloro-3-(3,5-diclorofenil) ciclo-propano carboxílico (C1)

Figure img0260
[000345] To a solution of trans-2-chloro-5-(2,2-dichloro-3-(3,4,5,-trichlorophenyl)cyclopropanecarboxamido)-N-(tetrahydrothiophen-3- yl)benzamide (F8) (0.150 g, 0.27 mmol) in glacial acetic acid (2.6 mL) was added sodium perborate tetrahydrate (0.0630 g, 0.282 mmol). The reaction was heated to 60°C and stirred for 4 hours. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane. The combined organic phases were dried over magnesium sulphate, filtered and concentrated. The residue was moistened in hexane and vacuum filtered to furnish the title compound as a yellowish brown powder (0.068 g, 44%). Example 36: Preparation of trans-2,2-dichloro-3-(3,5- dichlorophenyl) carboxylic cyclopropane (C1)
Figure img0260

[000346] Permanganato de sódio (40% aquoso) (84 g, 236 mmol) foi adicionado gota a gota a uma mistura agitada de trans-2,2-dicloro-3-(3,5- diclorofenil)ciclopropano-1-carbaldeído (C115) (58,7 g, 196 mmol) em acetona (982 mL) a 15°C. A mistura resultante foi agitada a 20°C por 2 horas. A mistura de reação foi diluída com álcool isopropílico (20 mL) e concentrada para remover a acetona. Celite® e ácido clorídrico aquoso (1 N, 295 mL, 295 mmol) foram adicionados ao resíduo marrom. A mistura resultante foi diluída com acetato de etila (500 mL) e filtrada através de Celite®. O filtrado foi lavado com solução salina (200 mL). A camada or-gânica foi seca com sulfato de sódio, filtrada e concentrada. A lama resultante foi diluída com heptano (~200 mL) e solidificada a 20°C. O sólido foi coletado, lavado com heptano e seco para resultar no produto do título como um sólido branco (54,68 g, 91%):1H RMN (300 MHz, CDCl3) δ 7,36 (t, J = 1,9 Hz, 1H), 7,17 (dd, J = 1,9, 0,7 Hz, 2H), 3,48 - 3,37 (m, 1H), 2,87 (d, J = 8,3 Hz, 1H); 13C RMN (400 MHz, CDCl3) δ 135,44, 135,28, 128,66, 127,30, 39,68, 36,88; ESIMS m/z = 298,9 ([M-H])-.[000346] Sodium permanganate (40% aqueous) (84 g, 236 mmol) was added dropwise to a stirred mixture of trans-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carbaldehyde (C115) (58.7 g, 196 mmol) in acetone (982 mL) at 15°C. The resulting mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with isopropyl alcohol (20 mL) and concentrated to remove acetone. Celite® and aqueous hydrochloric acid (1N, 295 mL, 295 mmol) were added to the brown residue. The resulting mixture was diluted with ethyl acetate (500 mL) and filtered through Celite®. The filtrate was washed with brine (200 ml). The organic layer was dried with sodium sulfate, filtered and concentrated. The resulting slurry was diluted with heptane (~200 mL) and solidified at 20°C. The solid was collected, washed with heptane and dried to give the title product as a white solid (54.68 g, 91%):1H NMR (300 MHz, CDCl3) δ 7.36 (t, J = 1.9 Hz, 1H), 7.17 (dd, J = 1.9, 0.7 Hz, 2H), 3.48 - 3.37 (m, 1H), 2.87 (d, J = 8.3 Hz , 1H); 13 C NMR (400 MHz, CDCl 3 ) δ 135.44, 135.28, 128.66, 127.30, 39.68, 36.88; ESIMS m/z = 298.9 ([M-H])-.

[000347] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 36:Ácido trans-2,2-Dicloro-3-(3,4,5-triclorofenil)ciclopropano-1-carboxílico (C2)

Figure img0261
[000347] The following compounds were prepared in a manner similar to the procedure described in Example 36: trans-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxylic acid (C2)
Figure img0261

[000348] Isolado como um sólido branco (2,78 g, 95%): 1H RMN (400 MHz, DMSO-d6) δ 13,41 (s, 1H), 7,81 (d, J = 0,6 Hz, 2H), 3,62 (d, J = 8,6 Hz, 1H), 3,52 (d, J = 8,6 Hz, 1H); ESIMS m/z 332 ([M-H]-).Ácido trans-2,2-Dicloro-3-(3,4-diclorofenil)ciclopropano-1-carboxílico (C3)

Figure img0262
[000348] Isolated as a white solid (2.78 g, 95%): 1H NMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 7.81 (d, J = 0.6 Hz , 2H), 3.62 (d, J = 8.6 Hz, 1H), 3.52 (d, J = 8.6 Hz, 1H); ESIMS m/z 332 ([MH]-). trans-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxylic acid (C3)
Figure img0262

[000349] Isolado como um sólido branco (124 g, 82%): pf 133 - 135°C: 1H RMN (500 MHz, DMSO-d6) δ 13,39 (s, 1H), 7,76 (d, J = 2,0 Hz, 1H), 7,64 (d, J = 8,3 Hz, 1H), 7,44 (dd, J = 8,4, 2,1 Hz, 1H), 3,49 (s, 2H). 13C RMN (126 MHz, DMSO-d6) δ 166,34, 133,35, 130,47, 130,33, 130,09, 129,77, 128,81, 61,43, 37,00, 36,06.Ácido trans-2,2-Dicloro-3-(3-cloro-4-fluorofenil)ciclopropano-1-carboxí- lico (C16)

Figure img0263
[000349] Isolated as a white solid (124 g, 82%): mp 133 - 135°C: 1H NMR (500 MHz, DMSO-d6) δ 13.39 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.44 (dd, J = 8.4, 2.1 Hz, 1H), 3.49 (s , 2H). 13C NMR (126 MHz, DMSO-d6) δ 166.34, 133.35, 130.47, 130.33, 130.09, 129.77, 128.81, 61.43, 37.00, 36.06 .trans-2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxylic acid (C16)
Figure img0263

[000350] Isolado como um sólido branco (165 g, 71%): 1H RMN (400 MHz, CDCl3) δ 11,57 (s, 1H), 7,42 (dd, J = 8,2, 7,6 Hz, 1H), 7,11 - 6,98 (m, 2H), 3,46 (d, J = 8,2 Hz, 1H), 2,85 (d, J = 8,3 Hz, 1H); 19F RMN (376 MHz, CDCl3) δ -114,07; ESIMS m/z 282 ([M-H]-).Ácido trans-2,2-Dicloro-3-(3-cloro-5-cianofenil)ciclopropano-1-carboxí- lico (C110)

Figure img0264
[000350] Isolated as a white solid (165 g, 71%): 1H NMR (400 MHz, CDCl 3 ) δ 11.57 (s, 1H), 7.42 (dd, J = 8.2, 7.6 Hz , 1H), 7.11 - 6.98 (m, 2H), 3.46 (d, J = 8.2 Hz, 1H), 2.85 (d, J = 8.3 Hz, 1H); 19F NMR (376 MHz, CDCl 3 ) δ -114.07; ESIMS m/z 282 ([MH]-). trans-2,2-Dichloro-3-(3-chloro-5-cyanophenyl)cyclopropane-1-carboxylic acid (C110)
Figure img0264

[000351] Isolado como um sólido branco (2,92 g, 60%): pf 173 - 175°C: 1H RMN (500 MHz, DMSO-d6) δ 13,42 (s, 1H), 8,03 (t, J = 1,7 Hz, 1H), 7,98 (t, J = 1,9 Hz, 2H), 3,65 (d, J = 8,6 Hz, 1H), 3,57 (d, J = 8,6 Hz, 1H); ESIMS m/z 290 ([M]).Exemplo 37: Preparação de ácido trans-2,2-dibromo-3-(3,5-diclorofenil) ciclo-propano-1-carboxílico (C111)

Figure img0265
[000351] Isolated as a white solid (2.92 g, 60%): mp 173 - 175°C: 1H NMR (500 MHz, DMSO-d6) δ 13.42 (s, 1H), 8.03 (t , J = 1.7 Hz, 1H), 7.98 (t, J = 1.9 Hz, 2H), 3.65 (d, J = 8.6 Hz, 1H), 3.57 (d, J = 8.6 Hz, 1H); ESIMS m/z 290 ([M]).Example 37: Preparation of trans-2,2-dibromo-3-(3,5-dichlorophenyl) cyclo-propane-1-carboxylic acid (C111)
Figure img0265

[000352] A uma solução de trans-2,2-dibromo-3-(3,5-diclorofenil) ci- clopropano-1-carbaldeído (C120) (1,67 g, 4,48 mmol) em acetonitrila (15,4 mL) e água (2,5 mL) foi adicionado sulfito de hidrogênio de sódio (3,26 g, 31,4 mmol). A solução resultante foi resfriada a 0°C, e clorito de sódio (3,54 g, 17,9 mmol) foi adicionado lentamente. A mistura foi agitada enquanto foi aquecida lentamente à temperatura ambiente durante a noite. A mistura foi então diluída com solução de ácido clorídrico aquoso (1 N) até que o pH fosse igual ou menor do que 3. A mistura foi então repetidamente extraída com acetato de etila e os extratos combinados secaram sobre sulfato de sódio, foram filtrados e concentrados a vácuo. A purificação do sólido bruto por cromatografia flash em coluna usando 0-100% de acetato de etila/hexanos como eluente forneceu o composto de título como um sólido marrom claro (0,91 g, 52%): 1H RMN (400 MHz, CDCl3) δ 7,36 (t, J = 1,9 Hz, 1H), 7,17 (dd, J = 1,9, 0,8 Hz, 2H), 3,39 (d, J = 8,2 Hz, 1H), 2,91 (d, J = 8,2 Hz, 1H); 13C RMN (101 MHz, CDCl3) δ 172,15, 136,91, 135,25, 128,64, 127,29, 40,29, 37,32, 26,57; ESIMS m/z 386 ([M-H]-).Exemplo 38: Preparação de ácido trans-2,2-dicloro-3-(3,5-diclorofenil)- 3-metilciclopropano-1-carboxílico (C112)

Figure img0266
[000352] To a solution of trans-2,2-dibromo-3-(3,5-dichlorophenyl)cyclopropane-1-carbaldehyde (C120) (1.67 g, 4.48 mmol) in acetonitrile (15, 4 mL) and water (2.5 mL) was added sodium hydrogen sulfite (3.26 g, 31.4 mmol). The resulting solution was cooled to 0°C, and sodium chlorite (3.54 g, 17.9 mmol) was added slowly. The mixture was stirred while slowly warming to room temperature overnight. The mixture was then diluted with aqueous hydrochloric acid solution (1N) until the pH was equal to or less than 3. The mixture was then repeatedly extracted with ethyl acetate and the combined extracts dried over sodium sulphate, filtered and vacuum concentrates. Purification of the crude solid by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent provided the title compound as a light brown solid (0.91 g, 52%): 1H NMR (400 MHz, CDCl 3 ) ) δ 7.36 (t, J = 1.9 Hz, 1H), 7.17 (dd, J = 1.9, 0.8 Hz, 2H), 3.39 (d, J = 8.2 Hz , 1H), 2.91 (d, J = 8.2 Hz, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 172.15, 136.91, 135.25, 128.64, 127.29, 40.29, 37.32, 26.57; ESIMS m/z 386 ([MH]-).Example 38: Preparation of trans-2,2-dichloro-3-(3,5-dichlorophenyl)-3-methylcyclopropane-1-carboxylic acid (C112)
Figure img0266

[000353] Trans-2,2-Dicloro-3-(3,5-diclorofenil)-3-metilciclopropil) metanol (C136) (1,16 g, 3,87 mmol) foi adicionado a uma solução em agitação do reagente de Jones (4,02 g, 18,6 mmol) em acetona (20 mL), a 5°C. A mistura foi agitada por 2 horas a 0-5°C e, em seguida, por 12 horas em temperatura ambiente. A suspensão marrom resultante foi arrefecida a 5°C e extinta com álcool isopropílico (20 mL), seguido de água (100 mL). A mistura foi extraída com acetato de etila (3 x 50 mL). Os extratos orgânicos combinados foram lavados com água e salmoura, secaram sobre sulfato de magnésio anidro, foram filtrados e concentrados em pressão reduzida em um evaporador rotativo. O produto bruto foi purificado por cromatografia flash C-18 com acetonitrila/água como eluente para obter ácido trans-2,2-dicloro-3-(3,5-diclorofenil)-3- metilciclopropanocarboxílico (0,727 g, 59%) como um sólido branco: 1H RMN (400 MHz, Acetona-d6) δ 7,49 (dd, J = 18,6, 1,9 Hz, 3H), 3,11 (s, 1H), 1,78 (s, 3H); 13C RMN (101 MHz, Acetona-d6) δ 166,55, 146,09, 135,70, 129,69, 128,49, 128,26, 66,75, 41,87, 39,59, 30,41, 30,21, 30,02, 29,83, 29,64, 29,55, 29,45, 29,25, 20,18; ESIMS m/z 313 ([M-H]-).[000353] Trans-2,2-Dichloro-3-(3,5-dichlorophenyl)-3-methylcyclopropyl) methanol (C136) (1.16 g, 3.87 mmol) was added to a stirred solution of the reagent. Jones (4.02 g, 18.6 mmol) in acetone (20 mL) at 5°C. The mixture was stirred for 2 hours at 0-5 °C and then for 12 hours at room temperature. The resulting brown suspension was cooled to 5°C and quenched with isopropyl alcohol (20ml), followed by water (100ml). The mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure on a rotary evaporator. The crude product was purified by C-18 flash chromatography with acetonitrile/water as eluent to obtain trans-2,2-dichloro-3-(3,5-dichlorophenyl)-3-methylcyclopropanecarboxylic acid (0.727 g, 59%) as a white solid: 1H NMR (400 MHz, Acetone-d6) δ 7.49 (dd, J = 18.6, 1.9 Hz, 3H), 3.11 (s, 1H), 1.78 (s, 3H ); 13C NMR (101 MHz, Acetone-d6) δ 166.55, 146.09, 135.70, 129.69, 128.49, 128.26, 66.75, 41.87, 39.59, 30.41 , 30.21, 30.02, 29.83, 29.64, 29.55, 29.45, 29.25, 20.18; ESIMS m/z 313 ([M-H]-).

[000354] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 38:Ácido cis-2,2-Dicloro-3-(3,5-diclorofenil)-3-metilciclopropano-1-carboxí- lico (C113)

Figure img0267
[000354] The following compounds were prepared in a manner similar to the procedure described in Example 38: cis-2,2-Dichloro-3-(3,5-dichlorophenyl)-3-methylcyclopropane-1-carboxylic acid (C113 )
Figure img0267

[000355] Isolado como um óleo incolor claro (0,088 g, 57%): 1H RMN (400 MHz, Acetona-d6) δ 7,60 - 7,27 (m, 3H), 2,81 (s, 1H), 1,77 (s, 3H); 13C RMN (101 MHz, Acetona-d6) δ 166,50, 141,92, 134,78, 129,66, 128,50, 128,26, 127,93, 67,25, 42,16, 41,58, 30,43, 30,24, 30,05, 29,97, 29,85, 29,77, 29,66, 29,57, 29,47, 29,28, 28,71, 20,20; ESIMS m/z 313 ([M-H]-). Ácido trans-2,2-Dicloro-3-(4-(nitrofenil)ciclopropano-1-carboxílico (C114)

Figure img0268
[000355] Isolated as a light colorless oil (0.088 g, 57%): 1H NMR (400 MHz, Acetone-d6) δ 7.60 - 7.27 (m, 3H), 2.81 (s, 1H), 1.77 (s, 3H); 13C NMR (101 MHz, Acetone-d6) δ 166.50, 141.92, 134.78, 129.66, 128.50, 128.26, 127.93, 67.25, 42.16, 41.58 , 30.43, 30.24, 30.05, 29.97, 29.85, 29.77, 29.66, 29.57, 29.47, 29.28, 28.71, 20.20; ESIMS m/z 313 ([MH]-). trans-2,2-Dichloro-3-(4-(nitrophenyl)cyclopropane-1-carboxylic acid (C114)
Figure img0268

[000356] Isolado como um sólido rosa (0,158 g, 48%): 1H RMN (400 MHz, CDCI3) δ 8,26 (d, J = 8,3 Hz, 2H), 7,47 (d, J = 8,4 Hz, 2H), 3,57 (d, J = 8,3 Hz, 1H), 2,98 (d, J = 8,3 Hz, 1H); 13C RMN (101 MHz, CDCl3) δ 171,34, 147,88, 139,21, 129,75, 123,85, 61,33, 40,14, 37,43; IR (película fina) 2923, 2603, 1709, 1601, 1520, 1446 cm-1; ESIMS m/z 273,9 ([M-H]-).Exemplo 39: Preparação de trans-2,2-dicloro-3-(3,5-diclorofenil)ciclo- propano-1-carbaldeído (C115)

Figure img0269
[000356] Isolated as a pink solid (0.158 g, 48%): 1H NMR (400 MHz, CDCl 3 ) δ 8.26 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8 0.4 Hz, 2H), 3.57 (d, J = 8.3 Hz, 1H), 2.98 (d, J = 8.3 Hz, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 171.34, 147.88, 139.21, 129.75, 123.85, 61.33, 40.14, 37.43; IR (thin film) 2923, 2603, 1709, 1601, 1520, 1446 cm-1; ESIMS m/z 273.9 ([MH]-).Example 39: Preparation of trans-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carbaldehyde (C115)
Figure img0269

[000357] Ácido clorídrico aquoso (2 N, 237 mL) foi adicionado a uma solução agitada de 1,3-dicloro-5-((trans- 2,2-dicloro-3-(dietoximetil) ci- clopropil)benzeno (C121) (85,7 g, 227 mmol) em acetonitrila (1184 mL). A mistura foi agitada a 20°C por 16 horas. A mistura resultante foi diluída com água (200 mL) e concentrada para remover a acetonitrila. A mistura aquosa resultante foi extraída com hexanos (600 mL). A camada orgânica foi lavada com água (300 mL), seca sobre sulfato de sódio, filtrada e concentrada. O produto bruto foi purificado por croma- tografia flash em coluna usando 0-20% de acetato de etila/hexanos como o eluente para resultar no produto do título como um óleo amarelo (58,7 g, 86%, 95% de pureza): 1H RMN (400 MHz, CDCl3) δ 9,54 (d, J = 4,0 Hz, 1H), 7,46 - 7,09 (m, 3H), 3,51 (d, J = 8,0 Hz, 1H), 2,92 (dd, J = 8,0, 4,0 Hz, 1H); 13C RMN (126 MHz, CDCl3) δ 193,41, 135,33, 135,09, 128,78, 127,34, 42,89, 39,31; IR (película fina) 3078, 2847, 1714, 1590, 1566, 1417, 1387.[000357] Aqueous hydrochloric acid (2N, 237 mL) was added to a stirred solution of 1,3-dichloro-5-((trans-2,2-dichloro-3-(diethoxymethyl)cyclopropyl)benzene (C121 ) (85.7 g, 227 mmol) in acetonitrile (1184 mL) The mixture was stirred at 20°C for 16 hours. The resulting mixture was diluted with water (200 mL) and concentrated to remove the acetonitrile. The resulting was extracted with hexanes (600 mL) The organic layer was washed with water (300 mL), dried over sodium sulfate, filtered and concentrated.The crude product was purified by flash column chromatography using 0-20% of ethyl acetate/hexanes as the eluent to give the title product as a yellow oil (58.7 g, 86%, 95% purity): 1 H NMR (400 MHz, CDCl 3 ) δ 9.54 (d, J = 4.0 Hz, 1H), 7.46 - 7.09 (m, 3H), 3.51 (d, J = 8.0 Hz, 1H), 2.92 (dd, J = 8.0, 4 .0 Hz, 1H); 13 C NMR (126 MHz, CDCl 3 ) δ 193.41, 135.33, 135.09, 128.78, 127.34, 42.89, 39.31; IR (thin film) 3078 , 2847, 1714, 1590, 1566, 1417, 1387.

[000358] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 39: trans-2,2-Dicloro-3-(3,4-diclorofenil)ciclopropano-1-carbaldeído (C116)

Figure img0270
[000358] The following compounds were prepared in a manner similar to the procedure described in Example 39: trans-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carbaldehyde (C116)
Figure img0270

[000359] Isolado como óleo laranja (143 g, 98%): 1H RMN (400 MHz, CDCl3) δ 9,53 (d, J = 4,1 Hz, 1H), 7,47 (d, J = 8,3 Hz, 1H), 7,37 (dd, J = 2,2, 0,7 Hz, 1H), 7,12 (ddd, J = 8,3, 2,2, 0,7 Hz, 1H), 3,51 (dd, J = 7,9, 0,8 Hz, 1H), 2,90 (dd, J = 8,0, 4,1 Hz, 1H).trans-2,2-Dicloro-3-(3-cloro-4-fluorofenil)ciclopropano-1-carbaldeído (C117)

Figure img0271
[000359] Isolated as orange oil (143 g, 98%): 1H NMR (400 MHz, CDCl 3 ) δ 9.53 (d, J = 4.1 Hz, 1H), 7.47 (d, J = 8. 3Hz, 1H), 7.37 (dd, J = 2.2, 0.7 Hz, 1H), 7.12 (ddd, J = 8.3, 2.2, 0.7 Hz, 1H), 3.51 (dd, J = 7.9, 0.8 Hz, 1H), 2.90 (dd, J = 8.0, 4.1 Hz, 1H). trans-2,2-Dichloro-3- (3-chloro-4-fluorophenyl)cyclopropane-1-carbaldehyde (C117)
Figure img0271

[000360] Isolado como um óleo laranja (230 g, 97%): 1H RMN (300 MHz, CDCI3) δ 9,52 (d, J = 4,2 Hz, 1H), 7,36 - 7,30 (m, 1H), 7,19 - 7,16 (m, 1H), 7,15 (d, J = 1,2 Hz, 1H), 3,51 (dt, J = 7,9, 0,7 Hz, 1H), 2,88 (dd, J = 7,9, 4,2 Hz, 1H).trans-2,2-Dicloro-3-(3,4,5-triclorofenil)ciclopropano-1-carbaldeído (C118)

Figure img0272
[000360] Isolated as an orange oil (230 g, 97%): 1H NMR (300 MHz, CDCl 3 ) δ 9.52 (d, J = 4.2 Hz, 1H), 7.36 - 7.30 (m , 1H), 7.19 - 7.16 (m, 1H), 7.15 (d, J = 1.2 Hz, 1H), 3.51 (dt, J = 7.9, 0.7 Hz, 1H), 2.88 (dd, J = 7.9, 4.2 Hz, 1H). trans-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carbaldehyde (C118)
Figure img0272

[000361] Isolado como um sólido amarelo (2,8 g, 69%): 1H RMN (400 MHz, CDCl3) δ 9,55 (d, J = 3,9 Hz, 1H), 7,30 (d, J = 0,7 Hz, 2H), 3,48 (dt, J = 8,0, 0,8 Hz, 1H), 2,92 (dd, J = 7,9, 3,9 Hz, 1H).trans-3-Cloro-5-(2,2-dicloro-3-formilciclopropil)benzonitrila (C119)

Figure img0273
[000361] Isolated as a yellow solid (2.8 g, 69%): 1H NMR (400 MHz, CDCl 3 ) δ 9.55 (d, J = 3.9 Hz, 1H), 7.30 (d, J = 0.7 Hz, 2H), 3.48 (dt, J = 8.0, 0.8 Hz, 1H), 2.92 (dd, J = 7.9, 3.9 Hz, 1H). trans -3-Chloro-5-(2,2-dichloro-3-formylcyclopropyl)benzonitrile (C119)
Figure img0273

[000362] Isolado como um sólido amarelo (2,9 g, 77%): 1H RMN (300 MHz, CDCl3) δ 9,59 (d, J = 3,6 Hz, 1H), 7,65 (ddd, J = 1,9, 1,4, 0,5 Hz, 1H), 7,52 (td, J = 1,8, 0,7 Hz, 1H), 7,48 (td, J = 1,5, 0,7 Hz, 1H), 3,56 (dq, J = 8,0, 0,6 Hz, 1H), 2,98 (dd, J = 8,0, 3,7 Hz, 1H).Exemplo 40: Preparação de trans-2,2-dibromo-3-(3,5-diclorofenil) ciclo- propano-1-carbaldeído (C120)

Figure img0274
[000362] Isolated as a yellow solid (2.9 g, 77%): 1 H NMR (300 MHz, CDCl 3 ) δ 9.59 (d, J = 3.6 Hz, 1H), 7.65 (ddd, J = 1.9, 1.4, 0.5 Hz, 1H), 7.52 (td, J = 1.8, 0.7 Hz, 1H), 7.48 (td, J = 1.5, 0 0.7 Hz, 1H), 3.56 (dq, J = 8.0, 0.6 Hz, 1H), 2.98 (dd, J = 8.0, 3.7 Hz, 1H). Example 40: Preparation of trans-2,2-dibromo-3-(3,5-dichlorophenyl) cyclopropane-1-carbaldehyde (C120)
Figure img0274

[000363] A uma solução de (E)-1,3-dicloro-5-(3,3-dietóxiprop-1-en-1- il)benzeno (C126) (500 mg, 1,817 mmol) em bromofórmio (12,1 mL) foram adicionados hexafluorofosfato de tetrabutilamônio (V) (70,4 mg, 0,182 mmol) seguido de adição cuidadosa de hidróxido de sódio sólido (1454 mg, 36,3 mmol). A mistura foi aquecida a 90°C em agitação durante a noite. A mistura foi então diluída com diclorometano e água e foi extraída com diclorometano adicional. A camada orgânica foi então seca com sulfato de sódio e concentrada. A purificação por cromato- grafia flash em coluna usando 0-100% de acetato de etila/hexanos como eluente forneceu um eluente resultante, que foi então dissolvido em acetona (4 mL) e ácido clorídrico aquoso (2 N, 1 mL, 2 mmol). A mistura foi agitada durante a noite. A mistura foi diluída com solução de bicarbonato de sódio saturado até que o pH da solução fosse maior do que 7. A mistura foi então extraída com éter dietílico e acetato de etila e as camadas orgânicas combinadas foram secas sobre sulfato de sódio e concentradas fornecendo o produto marrom escuro (0,03 g, 4%): 1H RMN (400 MHz, CDCl3) δ 9,48 (d, J = 4,0 Hz, 1H), 7,37 (t, J = 1,9 Hz, 1H), 7,17 (dd, J = 1,9, 0,7 Hz, 2H), 3,60 - 3,36 (m, 1H), 2,90 (dd, J = 7,9, 4,0 Hz, 1H); 13C RMN (101 MHz, CDCl3) δ 194,74, 136,55, 135,31, 128,76, 127,34, 42,34, 39,84, 26,05; ESIMS m/z 343 ([M- CHO]-).Exemplo 41: Preparação de 1,3-dicloro-5-(trans-2,2-dicloro-3-(dietóxi- metil)ciclopropil)benzeno (C121)

Figure img0275
[000363] To a solution of (E)-1,3-dichloro-5-(3,3-diethoxyprop-1-en-1-yl)benzene (C126) (500 mg, 1.817 mmol) in bromoform (12, 1 mL) was added tetrabutylammonium hexafluorophosphate (V) (70.4 mg, 0.182 mmol) followed by careful addition of solid sodium hydroxide (1454 mg, 36.3 mmol). The mixture was heated to 90°C under stirring overnight. The mixture was then diluted with dichloromethane and water and extracted with additional dichloromethane. The organic layer was then dried with sodium sulfate and concentrated. Purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent provided a resulting eluent, which was then dissolved in acetone (4 mL) and aqueous hydrochloric acid (2N, 1 mL, 2 mmol ). The mixture was stirred overnight. The mixture was diluted with saturated sodium bicarbonate solution until the pH of the solution was greater than 7. The mixture was then extracted with diethyl ether and ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated providing the dark brown product (0.03 g, 4%): 1H NMR (400 MHz, CDCl3) δ 9.48 (d, J = 4.0 Hz, 1H), 7.37 (t, J = 1.9 Hz , 1H), 7.17 (dd, J = 1.9, 0.7 Hz, 2H), 3.60 - 3.36 (m, 1H), 2.90 (dd, J = 7.9, 4 0.0Hz, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 194.74, 136.55, 135.31, 128.76, 127.34, 42.34, 39.84, 26.05; ESIMS m/z 343 ([M-CHO]-).Example 41: Preparation of 1,3-dichloro-5-(trans-2,2-dichloro-3-(diethoxymethyl)cyclopropyl)benzene (C121)
Figure img0275

[000364] Um balão de 4 bocas de 1L com um agitador mecânico, condensador, sonda de temperatura e entrada de nitrogênio foi carregado com (E)-1,3-dicloro-5-(3,3-dietóxiprop-1-en-1-il)benzeno (C126) (40 g, 138 mmol) e CHCl3 (447 mL). Foi adicionado hexafluorofosfato de tetrabutilamônio (1,081 g, 2,76 mmol). A solução amarela clara foi aquecida a 45°C. Com agitação vigorosa (~400 rpm), foi adicionado hidróxido de sódio aquoso (50%, 182 ml) em gotas através de funil de adição (durante 1 hora). Após 20 horas, a mistura foi deixada em arre-fecimento. A mistura foi diluída com hexano (200 mL). A camada orgânica superior foi decantada (fora da suspensão aquosa inferior) através de Celite®, lavando a torta de filtro com hexano (200 mL). O filtrado foi lavado com solução salina (~200 mL), seco sobre sulfato de sódio, filtrado e concentrado para fornecer o composto de título como um óleo marrom (50,2 g, 97%, 95% de pureza): 1H RMN (300 MHz, CDCl3) δ 7,31 (t, J = 1,9 Hz, 1H), 7,15 (dd, J = 1,9, 0,7 Hz, 2H), 4,59 (d, J = 6,2 Hz, 1H), 3,80 - 3,57 (m, 4H), 2,77 (d, J = 8,5 Hz, 1H), 2,25 (dd, J = 8,5, 6,2 Hz, 1H), 1,30 (t, J = 7,0 Hz, 3H), 1,20 (t, J = 7,1 Hz, 3H).[000364] A 1L 4-neck flask with a mechanical stirrer, condenser, temperature probe and nitrogen inlet was charged with (E)-1,3-dichloro-5-(3,3-diethoxyprop-1-en- 1-yl)benzene (C126) (40 g, 138 mmol) and CHCl3 (447 mL). Tetrabutylammonium hexafluorophosphate (1.081 g, 2.76 mmol) was added. The light yellow solution was heated to 45°C. With vigorous stirring (~400 rpm), aqueous sodium hydroxide (50%, 182 ml) was added dropwise via addition funnel (over 1 hour). After 20 hours the mixture was allowed to cool. The mixture was diluted with hexane (200 ml). The upper organic layer was decanted (out of the lower aqueous suspension) through Celite®, washing the filter cake with hexane (200 mL). The filtrate was washed with brine (~200 mL), dried over sodium sulfate, filtered and concentrated to provide the title compound as a brown oil (50.2 g, 97%, 95% purity): 1H NMR ( 300 MHz, CDCl3) δ 7.31 (t, J = 1.9 Hz, 1H), 7.15 (dd, J = 1.9, 0.7 Hz, 2H), 4.59 (d, J = 6.2 Hz, 1H), 3.80 - 3.57 (m, 4H), 2.77 (d, J = 8.5 Hz, 1H), 2.25 (dd, J = 8.5, 6 .2 Hz, 1H), 1.30 (t, J = 7.0 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H).

[000365] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 41:1,2-Dicloro-4-(trans-2,2-dicloro-3-(dietóximetil)ciclopropil)benzeno (C122)

Figure img0276
[000365] The following compounds were prepared in a manner similar to the procedure described in Example 41: 1,2-Dichloro-4-(trans-2,2-dichloro-3-(diethoxymethyl)cyclopropyl)benzene (C122)
Figure img0276

[000366] Isolado como um óleo marrom (184 g, 99%): 1H RMN (400 MHz, CDCl3) δ 7,43 (d, J = 8,2 Hz, 1H), 7,36 (dd, J = 2,2, 0,7 Hz, 1H), 7,10 (ddd, J = 8,3, 2,1, 0,7 Hz, 1H), 4,59 (d, J = 6,2 Hz, 1H), 3,82 - 3,55 (m, 4H), 2,77 (d, J = 8,5 Hz, 1H), 2,24 (dd, J = 8,5, 6,3 Hz, 1H), 1,30 (t, J = 7,0 Hz, 3H), 1,20 (t, J = 7,1 Hz, 3H).2-Cloro-4-(trans-2,2-dicloro-3-(dietóximetil)ciclopropil)-1-flúor-benzeno (C123)

Figure img0277
[000366] Isolated as a brown oil (184 g, 99%): 1 H NMR (400 MHz, CDCl 3 ) δ 7.43 (d, J = 8.2 Hz, 1H), 7.36 (dd, J = 2 .2, 0.7 Hz, 1H), 7.10 (ddd, J = 8.3, 2.1, 0.7 Hz, 1H), 4.59 (d, J = 6.2 Hz, 1H) , 3.82 - 3.55 (m, 4H), 2.77 (d, J = 8.5 Hz, 1H), 2.24 (dd, J = 8.5, 6.3 Hz, 1H), 1.30 (t, J = 7.0 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H). 2-Chloro-4-(trans-2,2-dichloro-3-( diethoxymethyl)cyclopropyl)-1-fluorobenzene (C123)
Figure img0277

[000367] Isolado como um óleo marrom (63 g, 96%): 1H RMN (400 MHz, CDCl3) δ 7,44 (dd, J = 7,0, 2,2 Hz, 1H), 7,29 - 7,22 (m, 1H), 7,09 (t, J = 8,7 Hz, 1H), 6,62 (dd, J = 16,1, 1,2 Hz, 1H), 6,14 (dd, J = 16,1, 5,0 Hz, 1H), 5,05 (dd, J = 4,9, 1,2 Hz, 1H), 3,70 (dq, J = 9,3, 7,0 Hz, 2H), 3,56 (dq, J = 9,4, 7,1 Hz, 2H), 1,25 (t, J = 7,1 Hz, 6H); 13C RMN (101 MHz, CDCl3) δ 158,91, 156,42, 133,65, 133,62, 130,47, 128,65, 128,07, 128,05, 126,39, 126,32, 121,26, 121,08, 116,72, 116,51, 100,93, 61,17, 15,24; 19F RMN (376 MHz, CDCl3) δ -116,36. 1,2,3-Tricloro-5-(trans-2,2-dicloro-3-(dietóximetil)ciclopropil)benzeno(C124)

Figure img0278
[000367] Isolated as a brown oil (63 g, 96%): 1H NMR (400 MHz, CDCl 3 ) δ 7.44 (dd, J = 7.0, 2.2 Hz, 1H), 7.29 - 7 .22 (m, 1H), 7.09 (t, J = 8.7 Hz, 1H), 6.62 (dd, J = 16.1, 1.2 Hz, 1H), 6.14 (dd, J = 16.1, 5.0 Hz, 1H), 5.05 (dd, J = 4.9, 1.2 Hz, 1H), 3.70 (dq, J = 9.3, 7.0 Hz , 2H), 3.56 (dq, J = 9.4, 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 158.91, 156.42, 133.65, 133.62, 130.47, 128.65, 128.07, 128.05, 126.39, 126.32, 121 .26, 121.08, 116.72, 116.51, 100.93, 61.17, 15.24; 19F NMR (376 MHz, CDCl3) δ -116.36. 1,2,3-Trichloro-5-(trans-2,2-dichloro-3-(diethoxymethyl)cyclopropyl)benzene(C124)
Figure img0278

[000368] Isolado como um óleo marrom (146 g, 93%): 1H RMN (400 MHz, CDCI3) δ 7,29 (d, J = 0,7 Hz, 2H), 4,59 (d, J = 6,1 Hz, 1H), 3,82 - 3,54 (m, 4H), 2,75 (d, J = 8,5 Hz, 1H), 2,23 (dd, J = 8,5, 6,1 Hz, 1H), 1,30 (t, J = 7,0 Hz, 3H), 1,20 (t, J = 7,0 Hz, 3H).3-Cloro-5-(trans-2,2-dicloro-3-(dietóximetil)ciclopropil)benzonitrila (C125)

Figure img0279
[000368] Isolated as a brown oil (146 g, 93%): 1 H NMR (400 MHz, CDCl 3 ) δ 7.29 (d, J = 0.7 Hz, 2H), 4.59 (d, J = 6 0.1Hz, 1H), 3.82 - 3.54 (m, 4H), 2.75 (d, J = 8.5 Hz, 1H), 2.23 (dd, J = 8.5, 6, 1 Hz, 1H), 1.30 (t, J = 7.0 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H). 3-Chloro-5-(trans-2.2 -dichloro-3-(diethoxymethyl)cyclopropyl)benzonitrile (C125)
Figure img0279

[000369] Isolado como um óleo amarelo (4,8 g, 74%): 1H RMN (400 MHz, CDCl3) δ 7,59 (t, J = 1,7 Hz, 1H), 7,50 (t, J = 1,9 Hz, 1H), 7,45 (t, J = 1,5 Hz, 1H), 4,61 (d, J = 6,0 Hz, 1H), 3,89 - 3,50 (m, 4H), 2,83 (d, J = 8,5 Hz, 1H), 2,28 (dd, J = 8,4, 6,0 Hz, 1H), 1,31 (t, J = 7,1 Hz, 3H), 1,21 (t, J = 7,0 Hz, 3H).Exemplo 42: Preparação de (E)-1,3-dicloro-5-(3,3-dietóxiprop-1-en-1- il)benzeno (C126)

Figure img0280
[000369] Isolated as a yellow oil (4.8 g, 74%): 1H NMR (400 MHz, CDCl 3 ) δ 7.59 (t, J = 1.7 Hz, 1H), 7.50 (t, J = 1.9 Hz, 1H), 7.45 (t, J = 1.5 Hz, 1H), 4.61 (d, J = 6.0 Hz, 1H), 3.89 - 3.50 (m , 4H), 2.83 (d, J = 8.5 Hz, 1H), 2.28 (dd, J = 8.4, 6.0 Hz, 1H), 1.31 (t, J = 7. 1 Hz, 3H), 1.21 (t, J = 7.0 Hz, 3H). Example 42: Preparation of (E)-1,3-dichloro-5-(3,3-diethoxyprop-1-en- 1-yl)benzene (C126)
Figure img0280

[000370] Etapa 1a: Acetaldeído (120 g, 2688 mmol) foi adicionado como uma mistura agitada de 3,5-diclorobenzaldeído (96 g, 538 mmol) em tolueno (400 mL) a 0°C. Uma solução de hidróxido de potássio (3,35 g, 53,8 mmol) em álcool metílico (10 mL) foi adicionada em gotas através de funil de adição. A mistura resultante foi agitada a 0°C durante 4 horas até que todo o 3,5-diclorobenzaldeído foi consumido por cromatografia de camada fina. Etapa 1b: Acetato de etila (500 mL) e ácido clorídrico concentrado (37% aquoso, 44,1 ml, 538 mmol) foram adicionados à mistura de reação. A mistura resultante foi aquecida a 80°C e um líquido incolor foi destilado (200 mL). A mistura de reação foi diluída com água (500 mL) e extraída com acetato de etila. A camada orgânica foi lavada com solução salina, seca sobre sulfato de sódio, filtrada e concentrada para proporcionar acrilaldeído de (E)-3- (3,5-diclorofenil) como um sólido amarelo claro (115 g) que foi usado diretamente sem posterior purificação: 1H RMN (300 MHz, CDCl3) δ 9,72 (dd, J = 7,4, 0,5 Hz, 1H), 7,43 (q, J = 1,8 Hz, 3H), 7,35 (d, J = 16,0 Hz, 1H), 6,69 (dd, J = 16,0, 7,4 Hz, 1H).[000370] Step 1a: Acetaldehyde (120 g, 2688 mmol) was added as a stirred mixture of 3,5-dichlorobenzaldehyde (96 g, 538 mmol) in toluene (400 mL) at 0°C. A solution of potassium hydroxide (3.35 g, 53.8 mmol) in methyl alcohol (10 mL) was added dropwise via addition funnel. The resulting mixture was stirred at 0°C for 4 hours until all of the 3,5-dichlorobenzaldehyde was consumed by thin layer chromatography. Step 1b: Ethyl acetate (500 mL) and concentrated hydrochloric acid (37% aqueous, 44.1 mL, 538 mmol) were added to the reaction mixture. The resulting mixture was heated to 80°C and a colorless liquid was distilled (200 ml). The reaction mixture was diluted with water (500 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to provide (E)-3-(3,5-dichlorophenyl) acrylaldehyde as a pale yellow solid (115 g) which was used directly without further purification: 1H NMR (300 MHz, CDCl3) δ 9.72 (dd, J = 7.4, 0.5 Hz, 1H), 7.43 (q, J = 1.8 Hz, 3H), 7.35 (d, J = 16.0 Hz, 1H), 6.69 (dd, J = 16.0, 7.4 Hz, 1H).

[000371] Etapa 2: Trietoximetano (31,4 g, 208 mmol) e piridina-1-io 4-metilbenzenossulfonato (0,528 g, 2,079 mmol) foram adicionados a uma solução agitada de (E)-3-(3,5-diclorofenil) acrilaldeído (44 g, 208 mmol) em etanol (416 mL). A mistura resultante foi agitada a 20°C durante 20 horas. Uma solução de carbonado de sódio aquoso saturado (50 mL) foi adicionada à mistura de reação. A mistura resultante foi concentrada em 45°C para remover o etanol. O concentrado foi diluído com água e extraído com hexano. A camada orgânica foi lavada com solução salina, seca sobre sulfato de sódio, filtrada e concentrada para proporcionar o produto de título como um óleo amarelo claro (56,13 g, 93%): 1H RMN (400 MHz, CDCl3) δ 7,25 (dt, J = 10,6, 1,9 Hz, 3H), 6,61 (dd, J = 16,1, 1,1 Hz, 1H), 6,22 (dd, J = 16,1, 4,7 Hz, 1H), 5,17 (s, 1H), 5,14 - 5,00 (m, 1H), 3,78 - 3,49 (m, 4H), 1,24 (q, J = 7,2 Hz, 6H); 13C RMN (101 MHz, CDCl3) δ 139,34, 135,14, 130,27, 129,88, 127,71, 125,08, 100,60, 61,20, 15,25.[000371] Step 2: Triethoxymethane (31.4 g, 208 mmol) and pyridine-1-io 4-methylbenzenesulfonate (0.528 g, 2.079 mmol) were added to a stirred solution of (E)-3-(3,5- dichlorophenyl)acrylaldehyde (44 g, 208 mmol) in ethanol (416 mL). The resulting mixture was stirred at 20°C for 20 hours. A saturated aqueous sodium carbonate solution (50 mL) was added to the reaction mixture. The resulting mixture was concentrated at 45°C to remove ethanol. The concentrate was diluted with water and extracted with hexane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to provide the title product as a pale yellow oil (56.13 g, 93%): 1H NMR (400 MHz, CDCl3) δ 7, 25 (dt, J = 10.6, 1.9 Hz, 3H), 6.61 (dd, J = 16.1, 1.1 Hz, 1H), 6.22 (dd, J = 16.1, 4.7 Hz, 1H), 5.17 (s, 1H), 5.14 - 5.00 (m, 1H), 3.78 - 3.49 (m, 4H), 1.24 (q, J =7.2Hz, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 139.34, 135.14, 130.27, 129.88, 127.71, 125.08, 100.60, 61.20, 15.25.

[000372] Os seguintes compostos foram preparados de maneira semelhante ao procedimento descrito no Exemplo 42:(E)-1,2-Dicloro-4-(3,3-dietóxiprop-1-en-1-il)benzeno(C127)

Figure img0281
[000372] The following compounds were prepared in a similar manner to the procedure described in Example 42: (E)-1,2-Dichloro-4-(3,3-diethoxyprop-1-en-1-yl)benzene(C127)
Figure img0281

[000373] Isolado como um óleo laranja (142 g, 91%): 1H RMN (300 MHz, CDCl3) δ 7,48 (d, J = 2,0 Hz, 1H), 7,39 (dd, J = 8,3, 0,8 Hz, 1H), 6,62 (d, J = 16,1 Hz, 1H), 6,20 (ddd, J = 16,1, 4,9, 0,8 Hz, 1H), 5,06 (dt, J = 4,9, 1,0 Hz, 1H), 3,78 - 3,48 (m, 4H), 1,25 (td, J = 7,1, 0,8 Hz, 6H).(E)-2-Cloro-4-(3,3-dietóxiprop-1-en-1-il)-1-fluorobenzeno (C128)

Figure img0282
[000373] Isolated as an orange oil (142 g, 91%): 1H NMR (300 MHz, CDCl 3 ) δ 7.48 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8 0.3, 0.8 Hz, 1H), 6.62 (d, J = 16.1 Hz, 1H), 6.20 (ddd, J = 16.1, 4.9, 0.8 Hz, 1H) , 5.06 (dt, J = 4.9, 1.0 Hz, 1H), 3.78 - 3.48 (m, 4H), 1.25 (td, J = 7.1, 0.8 Hz) , 6H). (E)-2-Chloro-4-(3,3-diethoxyprop-1-en-1-yl)-1-fluorobenzene (C128)
Figure img0282

[000374] Isolado como um óleo laranja (283 g, 84%): 1H RMN (400 MHz, CDCl3) δ 7,44 (dd, J = 7,0, 2,2 Hz, 1H), 7,29 - 7,22 (m, 1H), 7,09 (t, J = 8,7 Hz, 1H), 6,62 (dd, J = 16,1, 1,2 Hz, 1H), 6,14 (dd, J = 16,1, 5,0 Hz, 1H), 5,05 (dd, J = 4,9, 1,2 Hz, 1H), 3,70 (dq, J = 9,3, 7,0 Hz, 2H), 3,56 (dq, J = 9,4, 7,1 Hz, 2H), 1,25 (t, J = 7,1 Hz, 6H); 13C RMN (101 MHz, CDCl3) δ 158,91, 156,42, 133,65, 133,62, 130,47, 128,65, 128,07, 128,05, 126,39, 126,32, 121,26, 121,08, 116,72, 116,51, 100,93, 61,17, 15,24; 19F RMN (376 MHz, CDCl3) δ -116,36.(E)-1,2,3-Tricloro-5-(3,3-dietóxiprop-1-en-1-il)benzeno(C129)

Figure img0283
[000374] Isolated as an orange oil (283 g, 84%): 1H NMR (400 MHz, CDCl 3 ) δ 7.44 (dd, J = 7.0, 2.2 Hz, 1H), 7.29 - 7 .22 (m, 1H), 7.09 (t, J = 8.7 Hz, 1H), 6.62 (dd, J = 16.1, 1.2 Hz, 1H), 6.14 (dd, J = 16.1, 5.0 Hz, 1H), 5.05 (dd, J = 4.9, 1.2 Hz, 1H), 3.70 (dq, J = 9.3, 7.0 Hz , 2H), 3.56 (dq, J = 9.4, 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 158.91, 156.42, 133.65, 133.62, 130.47, 128.65, 128.07, 128.05, 126.39, 126.32, 121 .26, 121.08, 116.72, 116.51, 100.93, 61.17, 15.24; 19F NMR (376 MHz, CDCl3) δ -116.36.(E)-1,2,3-Trichloro-5-(3,3-diethoxyprop-1-en-1-yl)benzene(C129)
Figure img0283

[000375] Isolado como um óleo laranja (40 g, 91%): 1H RMN (400 MHz, CDCl3) δ 7,41 (s, 2H), 6,58 (dd, J = 16,1, 1,2 Hz, 1H), 6,21 (dd, J = 16,1, 4,6 Hz, 1H), 5,06 (dd, J = 4,7, 1,2 Hz, 1H), 3,69 (dq, J = 9,3, 7,1 Hz, 2H), 3,55 (dq, J = 9,5, 7,0 Hz, 2H), 1,25 (t, J = 7,1 Hz, 6H).(E)-3-Cloro-5-(3,3-dietóxiprop-1-en-1-il)benzonitrila (C130)

Figure img0284
[000375] Isolated as an orange oil (40 g, 91%): 1H NMR (400 MHz, CDCl 3 ) δ 7.41 (s, 2H), 6.58 (dd, J = 16.1, 1.2 Hz , 1H), 6.21 (dd, J = 16.1, 4.6 Hz, 1H), 5.06 (dd, J = 4.7, 1.2 Hz, 1H), 3.69 (dq, 1H), J = 9.3, 7.1 Hz, 2H), 3.55 (dq, J = 9.5, 7.0 Hz, 2H), 1.25 (t, J = 7.1 Hz, 6H). (E)-3-Chloro-5-(3,3-diethoxyprop-1-en-1-yl)benzonitrile (C130)
Figure img0284

[000376] Isolado como um óleo incolor (7,62 g, 62%): 1H RMN (400 MHz, CDCI3) δ 7,61 (t, J = 1,8 Hz, 1H), 7,58 - 7,53 (m, 1H), 7,51 (t, J = 1,7 Hz, 1H), 6,72 - 6,61 (m, 1H), 6,28 (dd, J = 16,1, 4,5 Hz, 1H), 5,09 (dd, J = 4,5, 1,3 Hz, 1H), 3,70 (dq, J = 9,4, 7,1 Hz, 2H), 3,56 (dq, J = 9,4, 7,0 Hz, 2H), 1,26 (t, J = 7,0 Hz, 6H).Exemplo 43: Preparação de etil-3-(3,5-diclorofenil)but-2-enoato (C131; razão de 85:15 de isômeros E e Z)

Figure img0285
[000376] Isolated as a colorless oil (7.62 g, 62%): 1H NMR (400 MHz, CDCl 3 ) δ 7.61 (t, J = 1.8 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.51 (t, J = 1.7 Hz, 1H), 6.72 - 6.61 (m, 1H), 6.28 (dd, J = 16.1, 4.5 Hz, 1H), 5.09 (dd, J = 4.5, 1.3 Hz, 1H), 3.70 (dq, J = 9.4, 7.1 Hz, 2H), 3.56 (dq , J = 9.4, 7.0 Hz, 2H), 1.26 (t, J = 7.0 Hz, 6H). Example 43: Preparation of ethyl-3-(3,5-dichlorophenyl)but-2 -enoate (C131; 85:15 ratio of E and Z isomers)
Figure img0285

[000377] Acetato de 2-(dietoxifosforil)etila (7,41 g, 33,1 mmol) foi adi-cionado gota a gota em uma mistura agitada de hidreto de sódio (60% de dispersão de óleo) (1,32 g, 33,1 mmol) em tetra-hidrofurano anidro (50 mL) a 5°C. Após a conclusão da adição, a solução resultante foi agitada por mais 30 minutos a 0°C, seguido pela agitação de 3,5- dicloroacetofenona (5,0 g, 26,5 mmol) dissolvido em tetra-hidrofurano (10 mL). A suspensão de óleo amarelo claro resultante foi agitada em temperatura ambiente por 12 horas. A reação foi extinta com cloreto de amônio aquoso saturado (100 mL). A mistura aquosa foi extraída com éter etílico (3 x 50 mL). Os extratos orgânicos combinados foram lavados com água e salmoura, secaram sobre sulfato de magnésio anidro, foram filtrados e concentrados em pressão reduzida em um evaporador rotativo. O produto bruto foi purificado por cromatografia de flash de gel de sílica (fase móvel de hexanos/acetato de etila) para obter etil-3-(3,5-diclorofenil)but-2-enoato (5,69 g, 79%) como uma mistura de isômeros E (85%) e Z- (15%).Exemplo 44: Preparação de (E)-3-(3,5-diclorofenil)but-2-en-1-ol (C132)

Figure img0286
[000377] 2-(Diethoxyphosphoryl)ethyl acetate (7.41 g, 33.1 mmol) was added dropwise into a stirred mixture of sodium hydride (60% oil dispersion) (1.32 g , 33.1 mmol) in anhydrous tetrahydrofuran (50 mL) at 5°C. Upon completion of the addition, the resulting solution was stirred for a further 30 minutes at 0°C, followed by stirring of 3,5-dichloroacetophenone (5.0 g, 26.5 mmol) dissolved in tetrahydrofuran (10 mL). The resulting pale yellow oil suspension was stirred at room temperature for 12 hours. The reaction was quenched with saturated aqueous ammonium chloride (100 mL). The aqueous mixture was extracted with ethyl ether (3 x 50 ml). The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure on a rotary evaporator. The crude product was purified by silica gel flash chromatography (mobile phase hexanes/ethyl acetate) to obtain ethyl-3-(3,5-dichlorophenyl)but-2-enoate (5.69 g, 79%) as a mixture of E (85%) and Z- (15%) isomers. Example 44: Preparation of (E)-3-(3,5-dichlorophenyl)but-2-en-1-ol (C132)
Figure img0286

[000378] Hidreto de Diisobutilalumínio (1,5 M de solução em tolueno, 33 mL, 48,3 mmol) foi adicionado gota a gota a uma solução agitada de etil-3-(3,5-diclorofenil)but-2-enoato (C131) (5,69 g, 21,95 mmol) em tolu- eno anidro (50 mL) a -78°C. Após a conclusão da adição, a solução ama-relada foi agitada a -78°C por mais 2 horas e, em seguida, foi deixada para aquecer em temperatura ambiente. Após 11 horas, a mistura de re-ação foi cuidadosamente extinta com ácido clorídrico aquoso (1 N, 50 mL) e extraída com tolueno (3 x 50 mL). Os extratos orgânicos combina-dos foram lavados com água e salmoura, secaram sobre sulfato de mag-nésio anidro, foram filtrados e concentrados em pressão reduzida em um evaporador rotativo. O produto bruto foi purificado por cromatografia de flash de gel de sílica (fase móvel de hexanos/acetato de etila) para obter (Z)-3-(3,5-diclorofenil)but-2-en-1-ol (0,316 g, 6,3 g) como um óleo incolor transparente e (E)-3-(3,5-diclorofenil)but-2-en-1-ol (1,59 g, 32%) como um óleo incolor transparente.Exemplo 45: Preparação de (E)-2-((3-(3,5-diclorofenil)but-2-en-1-il)óxi) tetra-hidro-2H-pirano (C133)

Figure img0287
[000378] Diisobutylaluminum hydride (1.5 M solution in toluene, 33 mL, 48.3 mmol) was added dropwise to a stirred solution of ethyl-3-(3,5-dichlorophenyl)but-2-enoate (C131) (5.69 g, 21.95 mmol) in anhydrous toluene (50 mL) at -78°C. Upon completion of the addition, the yellowish solution was stirred at -78°C for a further 2 hours and then allowed to warm to room temperature. After 11 hours the reaction mixture was carefully quenched with aqueous hydrochloric acid (1N, 50ml) and extracted with toluene (3x50ml). The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure on a rotary evaporator. The crude product was purified by silica gel flash chromatography (mobile phase hexanes/ethyl acetate) to obtain (Z)-3-(3,5-dichlorophenyl)but-2-en-1-ol (0.316 g , 6.3 g) as a clear colorless oil and (E)-3-(3,5-dichlorophenyl)but-2-en-1-ol (1.59 g, 32%) as a clear colorless oil. 45: Preparation of (E)-2-((3-(3,5-dichlorophenyl)but-2-en-1-yl)oxy)tetrahydro-2H-pyran (C133)
Figure img0287

[000379] 3,4-Di-hidro-2H-pirano (1,05, 12,45 mmol) foi adicionado gota a gota à solução agitada de (E)-3-(3,5-diclorofenil)but-2-en-1-ol (C132) (1,59 g, 7,32 mmol) e mono-hidrato de ácido p- toluenossul- fônico (0,07 g, 0,366 mmol) em éter anidro (50 mL) a 0°C. A solução foi deixada para aquecer a temperatura ambiente e foi agitada por mais 12 horas. A mistura de reação foi interrompida com água (100 mL) e extraída com éter (3 x 50 mL). Os extratos orgânicos combinados foram lavados com água e salmoura, secaram sobre sulfato de magnésio anidro, foram filtrados e concentrados em pressão reduzida em um evaporador rotativo para obter (E)-2-((3-(3,5- diclorofenil)but-2-en-1-il)óxi)tetra-hidro-2H-pirano (2,17 g, 93%) como um óleo incolor transparente.[000379] 3,4-Dihydro-2H-pyran (1.05, 12.45 mmol) was added dropwise to the stirred solution of (E)-3-(3,5-dichlorophenyl)but-2- en-1-ol (C132) (1.59 g, 7.32 mmol) and p-toluenesulfonic acid monohydrate (0.07 g, 0.366 mmol) in anhydrous ether (50 mL) at 0°C . The solution was allowed to warm to room temperature and stirred for a further 12 hours. The reaction mixture was quenched with water (100ml) and extracted with ether (3x50ml). The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure on a rotary evaporator to obtain (E)-2-((3-(3,5-dichlorophenyl)but- 2-en-1-yl)oxy)tetrahydro-2H-pyran (2.17 g, 93%) as a clear colorless oil.

[000380] Os seguintes compostos foram preparados de maneira semelhante ao procedimento descrito no Exemplo 45: (E)-2-((3-(4-Nitrofenil)alil)óxi)tetra-hidro-2H-pirano (C134)

Figure img0288
[000380] The following compounds were prepared in a similar manner to the procedure described in Example 45: (E)-2-((3-(4-Nitrophenyl)allyl)oxy)tetrahydro-2H-pyran (C134)
Figure img0288

[000381] Isolado como um óleo amarelo (2,25 g, 97%): 1H RMN (400 MHz, CDCI3) δ 8,26 - 8,09 (m, 2H), 7,57 - 7,44 (m, 2H), 6,79 - 6,63 (m, 1H), 6,51 (ddd, J = 16,0, 5,8, 5,2 Hz, 1H), 4,71 (dd, J = 4,2, 3,0 Hz, 1H), 4,46 (ddd, J = 13,9, 5,2, 1,7 Hz, 1H), 4,20 (ddd, J = 13,9, 5,9, 1,6 Hz, 1H), 3,91 (ddd, J = 11,2, 8,2, 3,3 Hz, 1H), 3,65 - 3,47 (m, 1H), 1,96 - 1,36 (m, 6H); 13C RMN (101 MHz, CDCl3) δ 146,95, 143,36, 131,36, 129,36, 126,93, 123,98, 98,33, 67,10, 62,34, 30,58, 25,41, 19,44; IR (película fina) 2939, 2849, 1595, 1513, 1339 cm-1.Exemplo 46: Preparação de trans-2-((2,2-dicloro-3-(3,5-diclorofenil)- 3-metilciclopropil)metóxi)tetra-hidro-2H-pirano (C135)

Figure img0289
[000381] Isolated as a yellow oil (2.25 g, 97%): 1H NMR (400 MHz, CDCl 3 ) δ 8.26 - 8.09 (m, 2H), 7.57 - 7.44 (m, 2H), 6.79 - 6.63 (m, 1H), 6.51 (ddd, J = 16.0, 5.8, 5.2 Hz, 1H), 4.71 (dd, J = 4, 2, 3.0 Hz, 1H), 4.46 (ddd, J = 13.9, 5.2, 1.7 Hz, 1H), 4.20 (ddd, J = 13.9, 5.9, 1.6 Hz, 1H), 3.91 (ddd, J = 11.2, 8.2, 3.3 Hz, 1H), 3.65 - 3.47 (m, 1H), 1.96 - 1 .36 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 146.95, 143.36, 131.36, 129.36, 126.93, 123.98, 98.33, 67.10, 62.34, 30.58, 25 .41, 19.44; IR (thin film) 2939, 2849, 1595, 1513, 1339 cm-1.Example 46: Preparation of trans-2-((2,2-dichloro-3-(3,5-dichlorophenyl)-3-methylcyclopropyl)methoxy )tetrahydro-2H-pyran (C135)
Figure img0289

[000382] Hidróxido de sódio em pó (2,92 g, 73 mmol) foi adicionado porção a porção a uma solução em agitação de (E)-2-((3-(3,5- diclorofenil)but-2-en-1-il)óxi)tetra-hidro-2H-pirano (C133) (2,17 g, 7,3 mmol) e hexafluorofosfato de tetrabutilamônio (V) (0,283 g, 0,730 mmol) em clorofórmio (20 mL). A suspensão amarela resultante de sólidos foi aquecida a 55°C em um total de 7 horas e foi agitada em temperatura ambiente por mais 12 horas. A mistura de reação foi interrompida com água (100 mL) e extraída com éter (3 x 50 mL). Os extratos orgânicos combinados foram lavados com água e salmoura, secaram sobre sulfato de magnésio anidro, foram filtrados e concentrados em pressão reduzida em um evaporador rotativo. O produto bruto foi purificado por cromatografia de flash de gel de sílica (fase móvel de hexanos/acetato de etila) para obter trans-2-((2,2-dicloro-3-(3,5-diclo- rofenil)-3-metilciclopropil)metóxi)tetra-hidro-2H-pirano (2,03 g, 69%) como um óleo incolor transparente.Exemplo 47: Preparação de trans-2,2-dicloro-3-(3,5-diclorofenil)-3- metilciclopropil)metanol (C136)

Figure img0290
[000382] Sodium hydroxide powder (2.92 g, 73 mmol) was added portionwise to a stirred solution of (E)-2-((3-(3,5-dichlorophenyl)but-2-en -1-yl)oxy)tetrahydro-2H-pyran (C133) (2.17 g, 7.3 mmol) and tetrabutylammonium hexafluorophosphate (V) (0.283 g, 0.730 mmol) in chloroform (20 mL). The resulting yellow suspension of solids was heated to 55°C for a total of 7 hours and stirred at room temperature for a further 12 hours. The reaction mixture was quenched with water (100ml) and extracted with ether (3x50ml). The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure on a rotary evaporator. The crude product was purified by silica gel flash chromatography (mobile phase hexanes/ethyl acetate) to obtain trans-2-((2,2-dichloro-3-(3,5-dichlorophenyl)-3 -methylcyclopropyl)methoxy)tetrahydro-2H-pyran (2.03 g, 69%) as a clear colorless oil. Example 47: Preparation of trans-2,2-dichloro-3-(3,5-dichlorophenyl)- 3-methylcyclopropyl)methanol (C136)
Figure img0290

[000383] Mono-hidrato de ácido p- toluenossulfônico (0,101 g, 0,528 mmol) foi adicionado a uma solução em agitação de trans-2-((2,2- dicloro-3-(3,5-diclorofenil)-3-metilciclopropil)metóxi)tetra-hidro-2H- pirano (C135) (2,03 g, 5,28 mmol) em metanol (20 mL). A mistura foi agitada por 11 horas em temperatura ambiente e, em seguida, foi con-centrada a vácuo em um evaporador rotativo. Purificação por cromato- grafia de flash de gel de sílica (fase móvel de hexanos/acetato de etila) obteve trans-2,2-dicloro-3-(3,5-diclorofenil)-3-metilciclopropil)metanol (1,16 g, 70%) como um óleo amarelo claro.Exemplo 48: Preparação de trans-(2,2-dicloro-3-(4-nitrofenil)ciclopropil) -metanol (C137)

Figure img0291
[000383] p-Toluenesulfonic acid monohydrate (0.101 g, 0.528 mmol) was added to a stirred solution of trans-2-((2,2-dichloro-3-(3,5-dichlorophenyl)-3- methylcyclopropyl)methoxy)tetrahydro-2H-pyran (C135) (2.03 g, 5.28 mmol) in methanol (20 mL). The mixture was stirred for 11 hours at room temperature and then concentrated in vacuo on a rotary evaporator. Purification by silica gel flash chromatography (mobile phase hexanes/ethyl acetate) gave trans-2,2-dichloro-3-(3,5-dichlorophenyl)-3-methylcyclopropyl)methanol (1.16 g , 70%) as a pale yellow oil.Example 48: Preparation of trans-(2,2-dichloro-3-(4-nitrophenyl)cyclopropyl)-methanol (C137)
Figure img0291

[000384] A uma solução agitada de (E)-2-((3-(4-nitrofenil)óxi)tetra- hidro-2H-pirano (C134) (0,5 g, 1,899 mmol) e hexafluorofosfato de tetra- butilamônio (V) (0,037 g, 0,095 mmol) em clorofórmio (6,33 mL) foi adici-onado hidróxido de sódio em pó (1,139 g, 28,5 mmol) e a mistura de rea-ção foi agitada com vigor em temperatura ambiente por 18 horas. A mis-tura de reação foi diluída com água e diclorometano e as camadas foram separadas. A camada orgânica foi concentrada e purificada por cromato- grafia de coluna de flash obtendo 2-((trans-2,2-dicloro-3-(4- nitrofenil)ciclopropil)metóxi)-tetra-hidro-2H-pirano como uma mistura de diastereômeros. A mistura foi dissolvida em metanol (10 mL). À solução de metanol foi adicionado ácido p- toluenossulfônico (0,020 g, 0,107 mmol), e a mistura de reação foi agitada em temperatura ambiente por 18 horas. A mistura de reação foi interrompida com bicarbonato de sódio saturado e foi extraída com acetato de etila (2x). As fases orgânicas combinadas foram secas sobre sulfato de magnésio, filtradas e concen-tradas para render o composto do título como um óleo amarelo (310 mg, 53% em 2 etapas): 1H RMN (400 MHz, CDCI3) δ 8,22 (d, J = 8,7 Hz, 2H), 7,52 - 7,34 (m, 2H), 4,10 (ddd, J = 12,4, 7,2, 5,3 Hz, 1H), 3,95 (ddd, J = 12,0, 8,0, 5,0 Hz, 1H), 2,78 (d, J = 8,3 Hz, 1H), 2,37 (td, J = 8,2, 5,4 Hz, 1H); 13C RMN (101 MHz, CDCI3) δ 147,43, 141,42, 129,77, 123,59, 63,74, 62,25, 38,50, 37,04; IR (película fina) 1598, 1514, 1345, 1046 cm- 1; HRMS-ESI (m/z) [M+Na]+ calculado para C10H9Cl2NO3Na, 283,9852; encontrado, 283,9844.Exemplo 49: Preparação de 1-bromo-2-cloro-4-(trans-2,2-dicloro-3-(4- metoxifenil)ciclopropil)benzeno (C138)

Figure img0292
[000384] To a stirred solution of (E)-2-((3-(4-nitrophenyl)oxy)tetrahydro-2H-pyran (C134) (0.5 g, 1.899 mmol) and tetrabutylammonium hexafluorophosphate (V) (0.037 g, 0.095 mmol) in chloroform (6.33 mL) was added powdered sodium hydroxide (1.139 g, 28.5 mmol) and the reaction mixture was stirred vigorously at room temperature. for 18 hours. The reaction mixture was diluted with water and dichloromethane and the layers were separated. The organic layer was concentrated and purified by flash column chromatography obtaining 2-((trans-2,2-dichloro-). 3-(4-nitrophenyl)cyclopropyl)methoxy)-tetrahydro-2H-pyran as a mixture of diastereomers.The mixture was dissolved in methanol (10 mL) To the methanol solution was added p-toluenesulfonic acid (0.020 g, 0.107 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (2x). dried over magnesium sulfate, filtered and concentrated to yield the title compound as a yellow oil (310 mg, 53% over 2 steps): 1H NMR (400 MHz, CDCl 3 ) δ 8.22 (d, J = 8 0.7 Hz, 2H), 7.52 - 7.34 (m, 2H), 4.10 (ddd, J = 12.4, 7.2, 5.3 Hz, 1H), 3.95 (ddd, J = 12.0, 8.0, 5.0 Hz, 1H), 2.78 (d, J = 8.3 Hz, 1H), 2.37 (td, J = 8.2, 5.4 Hz , 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 147.43, 141.42, 129.77, 123.59, 63.74, 62.25, 38.50, 37.04; IR (thin film) 1598, 1514, 1345, 1046 cm-1; HRMS-ESI (m/z) [M+Na]+ calculated for C10H9Cl2NO3Na, 283.9852; found, 283.9844. Example 49: Preparation of 1-bromo-2-chloro-4-(trans-2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)benzene (C138)
Figure img0292

[000385] A uma solução agitada de (E)-1-bromo-2-cloro-4-(4-meto- xistiril)benzeno (C142) (0,38 g, 1,174 mmol) e hexafluorofosfato de te- trabutilamônio (V) (0,045 g, 0,117 mmol) em clorofórmio (5,61 g, 3,77 mL, 47,0 mmol) foi adicionado hidróxido de sódio aquoso (50%, 2,348 g, 29,4 mmol) e a mistura resultante foi agitada vigorosamente em temperatura ambiente por 40 horas. A mistura de reação foi diluída com água e foi extraída com diclorometano. As camadas orgânicas combinadas foram secas sobre sulfato de sódio, filtradas e concentradas. A purificação por cromatografia flash em coluna usando 0-10% de acetato de etila/hexanos como eluente forneceu o composto do título como um óleo incolor (0,362 g, 72%): 1H RMN (400 MHz, CDCl3) δ7,62 (d, J = 8,3 Hz, 1H), 7,46 (d, J = 2,0 Hz, 1H), 7,29 - 7,23 (m, 2H),7,13 (dd, J = 8,3, 2,1 Hz, 1H), 6,93 (d, J = 8,7 Hz, 2H), 3,83 (s, 3H), 3,12 (d, J = 8,7 Hz, 1H), 3,07 (d, J = 8,7 Hz, 1H); 13C RMN (101 MHz,CDCl3) δ 159,43, 135,68, 134,63, 133,68, 130,80, 129,90, 128,49,125,81, 121,83, 114,01, 64,86, 55,33, 39,54, 38,85; IR (película fina) 3356 (br), 3002, 2835, 1514, 1248 cm-1.[000385] To a stirred solution of (E)-1-bromo-2-chloro-4-(4-methoxystyryl)benzene (C142) (0.38 g, 1.174 mmol) and tetrabutylammonium hexafluorophosphate (V ) (0.045 g, 0.117 mmol) in chloroform (5.61 g, 3.77 mL, 47.0 mmol) was added aqueous sodium hydroxide (50%, 2.348 g, 29.4 mmol) and the resulting mixture was stirred vigorously at room temperature for 40 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by flash column chromatography using 0-10% ethyl acetate/hexanes as eluent provided the title compound as a colorless oil (0.362 g, 72%): 1H NMR (400 MHz, CDCl3) δ7.62 (d , J = 8.3 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.29 - 7.23 (m, 2H), 7.13 (dd, J = 8. 3. 2.1 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 3.83 (s, 3H), 3.12 (d, J = 8.7 Hz, 1H) , 3.07 (d, J = 8.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 159.43, 135.68, 134.63, 133.68, 130.80, 129.90, 128.49,125.81, 121.83, 114.01, 64.86 , 55.33, 39.54, 38.85; IR (thin film) 3356 (br), 3002, 2835, 1514, 1248 cm-1.

[000386] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 49:2-Bromo-5-(trans-2,2-dicloro-3-(4-(metoxifenil)ciclopropil)-1,3-difluoro- benzeno (C139)

Figure img0293
[000386] The following compounds were prepared in a manner similar to the procedure described in Example 49: 2-Bromo-5-(trans-2,2-dichloro-3-(4-(methoxyphenyl)cyclopropyl)-1,3- difluorobenzene (C139)
Figure img0293

[000387] Isolado como um sólido amarelo (3,44 g, 79%): pf 104,0 - 109,3°C; 1H RMN (400 MHz, CDCl3) δ 7,28 - 7,22 (m, 2H), 7,02 - 6,96 (m, 2H), 6,96 - 6,90 (m, 2H), 3,83 (s, 3H), 3,12 (d, J = 8,7 Hz, 1H), 3,08 (d, J = 8,7 Hz, 1H); 13C RMN (101 MHz, CDCl3) δ 161,10, 159,49, 129,86, 125,47, 114,04, 112,79, 112,56, 112,53, 64,66, 55,33, 39,77, 39,01; 19F RMN (376 MHz, CDCl3) δ -104,75.2-Bromo-5-(trans-2,2-dicloro-3-(4-metoxifenil)ciclopropil)-1-flúor-3- metoxibenzeno (C140)

Figure img0294
[000387] Isolated as a yellow solid (3.44 g, 79%): mp 104.0 - 109.3°C; 1H NMR (400 MHz, CDCl 3 ) δ 7.28 - 7.22 (m, 2H), 7.02 - 6.96 (m, 2H), 6.96 - 6.90 (m, 2H), 3. 83 (s, 3H), 3.12 (d, J = 8.7 Hz, 1H), 3.08 (d, J = 8.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 161.10, 159.49, 129.86, 125.47, 114.04, 112.79, 112.56, 112.53, 64.66, 55.33, 39 .77, 39.01; 19F NMR (376 MHz, CDCl3) δ -104.75.2-Bromo-5-(trans-2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)-1-fluor-3-methoxybenzene (C140)
Figure img0294

[000388] Isolado como um óleo amarelo (1,18 g, 76%): 1H RMN (400 MHz, CDCI3) δ 7,30 - 7,26 (m, 2H), 6,96 - 6,91 (m, 2H), 6,80 - 6,74 (m, 1H), 6,70 (d, J = 1,6 Hz, 1H), 3,96 (s, 3H), 3,83 (s, 3H), 3,15 - 3,07 (m, 2H); 13C RMN (101 MHz, CDCl3) δ 161,20, 159,43, 136,09, 135,99, 129,91, 125,85, 114,01, 109,29, 109,05, 108,20, 64,91, 56,79, 55,33, 39,59, 39,49; 19F RMN (376 MHz, CDCl3) δ -104,96.1-Bromo-5-(trans-(2,2-dicloro-3-(4-metoxifenil)ciclopropil)-3-flúor-2- metoxibenzeno (C141)

Figure img0295
[000388] Isolated as a yellow oil (1.18 g, 76%): 1H NMR (400 MHz, CDCl 3 ) δ 7.30 - 7.26 (m, 2H), 6.96 - 6.91 (m, 2H), 6.80 - 6.74 (m, 1H), 6.70 (d, J = 1.6 Hz, 1H), 3.96 (s, 3H), 3.83 (s, 3H), 3.15 - 3.07 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 161.20, 159.43, 136.09, 135.99, 129.91, 125.85, 114.01, 109.29, 109.05, 108.20, 64 .91, 56.79, 55.33, 39.59, 39.49; 19F NMR (376 MHz, CDCl3) δ -104.96.1-Bromo-5-(trans-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)-3-fluoro-2-methoxybenzene (C141)
Figure img0295

[000389] Isolado como um óleo amarelo (0,37 g, 59%): 1H RMN (400 MHz, CDCI3) δ 7,31 - 7,23 (m, 3H), 6,98 (d, J = 11,6 Hz, 1H), 6,96 - 6,90 (m, 2H), 3,92 (s, 3H), 3,83 (s, 3H), 3,13 (d, J = 8,8 Hz, 1H), 3,07 (d, J = 8,8 Hz, 1H); 13C RMN (101 MHz, CDCl3) δ 159,38, 152,57, 147,73, 129,93, 127,93, 125,93, 120,63, 117,66, 117,23, 113,97, 65,40, 56,57, 55,33, 40,10, 39,59; 19F RMN (376 MHz, CDCl3) δ -135,58.Exemplo 50: Preparação de (E)-1-bromo-2-cloro-4-(4-metoxiestiril) benzeno (C142)

Figure img0296
[000389] Isolated as a yellow oil (0.37 g, 59%): 1H NMR (400 MHz, CDCl 3 ) δ 7.31 - 7.23 (m, 3H), 6.98 (d, J = 11. 6Hz, 1H), 6.96 - 6.90 (m, 2H), 3.92 (s, 3H), 3.83 (s, 3H), 3.13 (d, J = 8.8 Hz, 1H), 3.07 (d, J = 8.8 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 159.38, 152.57, 147.73, 129.93, 127.93, 125.93, 120.63, 117.66, 117.23, 113.97, 65 .40, 56.57, 55.33, 40.10, 39.59; 19F NMR (376 MHz, CDCl3) δ -135.58. Example 50: Preparation of (E)-1-bromo-2-chloro-4-(4-methoxystyryl)benzene (C142)
Figure img0296

[000390] A uma solução agitada de dietil (4-metoxibenzil)fosfonato (0,619 g, 2,73 mmol) em N,N-dimetilformamida (3 mL) a 0°C, foi adicionada uma solução de metóxido de sódio (5,4 M em metanol, 0,844 mL, 4,56 mmol). 4-Bromo-3-clorobenzaldeído (0,5 g, 2,278 mmol) em N,N-dimetilformamida (1 mL) foi adicionado e a mistura de reação foi aquecida a 65°C por 4 horas. A mistura de reação foi deixada resfriar em temperatura ambiente e foi partilhada entre água e acetato de etila. A camada orgânica foi seca sobre sulfato de magnésio, filtrada e concentrada. Purificação por cromatografia de coluna de flash usando 0-10% de acetato de etila/hexanos como o eluente forneceu o composto do título como um sólido cristalino amarelo (0,484 g, 59%): pf 77 - 88°C; 1H RMN (400 MHz, CDCl3) δ 7,58 - 7,53 (m, 2H), 7,47 - 7,39 (m, 2H), 7,22 (dd, J = 8,4, 2,1 Hz, 1H), 7,06 (d, J = 16,2 Hz, 1H), 6,95 - 6,87 (m, 2H), 6,84 (d, J = 16,3 Hz, 1H), 3,84 (s, 3H); EIMS m/z 324.Exemplo 51: Preparação de (E)-2-bromo-1,3-difluoro-5-(4- metoxistiril) benzeno (C143) e (E)-2-bromo-1-flúor-3-metóxi-5-(4- metoxistiril)benzeno (C144)

Figure img0297
[000390] To a stirred solution of diethyl(4-methoxybenzyl)phosphonate (0.619 g, 2.73 mmol) in N,N-dimethylformamide (3 mL) at 0°C was added a solution of sodium methoxide (5, 4M in methanol, 0.844ml, 4.56mmol). 4-Bromo-3-chlorobenzaldehyde (0.5 g, 2.278 mmol) in N,N-dimethylformamide (1 mL) was added and the reaction mixture was heated at 65°C for 4 hours. The reaction mixture was allowed to cool to room temperature and was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by flash column chromatography using 0-10% ethyl acetate/hexanes as the eluent furnished the title compound as a yellow crystalline solid (0.484 g, 59%): mp 77 - 88°C; 1H NMR (400 MHz, CDCl 3 ) δ 7.58 - 7.53 (m, 2H), 7.47 - 7.39 (m, 2H), 7.22 (dd, J = 8.4, 2.1 Hz, 1H), 7.06 (d, J = 16.2 Hz, 1H), 6.95 - 6.87 (m, 2H), 6.84 (d, J = 16.3 Hz, 1H), 3.84 (s, 3H); EIMS m/z 324.Example 51: Preparation of (E)-2-bromo-1,3-difluoro-5-(4-methoxystyril)benzene (C143) and (E)-2-bromo-1-fluor-3 -methoxy-5-(4-methoxystyryl)benzene (C144)
Figure img0297

[000391] A uma solução agitada de dietil (4-metoxibenzil)fosfonato (5,54 g, 24,43 mmol) em N,N-dimetilformamida (27 mL) a 0°C foi adicionada uma solução de metóxido de sódio (5,4 M em metanol, 4,52 mL, 24,43 mmol). 4-Bromo-3,5-difluorobenzaldeído (4,5 g, 20,36 mmol) em N,N-dimetilformamida (9 mL) foi adicionado e a mistura de reação foi aquecida a 65°C por 1 hora. A mistura de reação foi deixada resfriar em temperatura ambiente e foi partilhada entre água e acetato de etila. A camada orgânica foi seca sobre sulfato de magnésio, filtrada e con-centrada. Purificação por cromatografia em coluna de flash usando 010% de acetato de etila/hexanos como eluente forneceu (E)-2-bromo- 1,3-difluoro-5-(4-metoxistiril)benzeno (C143) como um sólido branco (3,28 g, 47%) e (E)-2-bromo-1-flúor-3-metóxi-5-(4-metoxistiril)benzeno (C144) como um sólido branco (1,19 g, 16%). C143: pf 104,1-112,7°C; 1H RMN (400 MHz, CDCh) δ 7,48 - 7,41 (m, 2H), 7,10 - 7,02 (m, 3H), 6,94 - 6,88 (m, 2H), 6,82 (d, J = 16,2 Hz, 1H), 3,84 (s, 3H); 19F RMN (376 MHz, CDCl3) δ -106,11; EIMS m/z 324,0. C144: pf 118,5-123,0°C; 1H RMN (400 MHz, CDCl3) δ 7,45 (d, J = 8,6 Hz, 2H), 7,06 (d, J = 16,2 Hz, 1H), 6,91 (dd, J = 9,1, 2,2 Hz, 3H), 6,86 (d, J = 16,2 Hz, 1H), 6,78 (t, J = 1,5 Hz, 1H), 3,96 (s, 3H), 3,84 (s, 3H); 19F RMN (376 MHz, CDCl3) δ -106,15; EIMS m/z 336,0.Exemplo 52: Preparação de (E)-1-bromo-3-flúor-2-metóxi-5-(4-metóxi- estiril)benzeno (C145)

Figure img0298
[000391] To a stirred solution of diethyl (4-methoxybenzyl)phosphonate (5.54 g, 24.43 mmol) in N,N-dimethylformamide (27 mL) at 0°C was added a solution of sodium methoxide (5 .4M in methanol, 4.52ml, 24.43mmol). 4-Bromo-3,5-difluorobenzaldehyde (4.5 g, 20.36 mmol) in N,N-dimethylformamide (9 mL) was added and the reaction mixture was heated at 65°C for 1 hour. The reaction mixture was allowed to cool to room temperature and was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by flash column chromatography using 010% ethyl acetate/hexanes as eluent provided (E)-2-bromo-1,3-difluoro-5-(4-methoxystyryl)benzene (C143) as a white solid (3 .28 g, 47%) and (E)-2-bromo-1-fluoro-3-methoxy-5-(4-methoxystyryl)benzene (C144) as a white solid (1.19 g, 16%). C143: mp 104.1-112.7°C; 1H NMR (400 MHz, CDCh) δ 7.48 - 7.41 (m, 2H), 7.10 - 7.02 (m, 3H), 6.94 - 6.88 (m, 2H), 6. 82 (d, J = 16.2 Hz, 1H), 3.84 (s, 3H); 19F NMR (376 MHz, CDCl 3 ) δ -106.11; EIMS m/z 324.0. C144: mp 118.5-123.0°C; 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 16.2 Hz, 1H), 6.91 (dd, J = 9 .1, 2.2 Hz, 3H), 6.86 (d, J = 16.2 Hz, 1H), 6.78 (t, J = 1.5 Hz, 1H), 3.96 (s, 3H ), 3.84 (s, 3H); 19F NMR (376 MHz, CDCl 3 ) δ -106.15; EIMS m/z 336.0.Example 52: Preparation of (E)-1-bromo-3-fluoro-2-methoxy-5-(4-methoxystyryl)benzene (C145)
Figure img0298

[000392] A uma solução agitada de dietil (4-metoxibenzil)fosfonato (1,85 mL, 8,14 mmol) em N,N-dimetilformamida (9 mL) a 0°C, foi adicionada uma solução de metóxido de sódio (5,4 M em metanol, 1,38 mL, 7,47 mmol). 3-Bromo-4,5-fluorobenzaldeído (1,5 g, 6,79 mmol) em N,N-dimetilformamida (3 mL) foi adicionado e a mistura de reação foi aquecida a 65°C por 2 horas. A mistura de reação foi deixada resfriar em temperatura ambiente e foi partilhada entre água e acetato de etila. A camada orgânica foi seca sobre sulfato de magnésio, filtrada e concentrada. Purificação por cromatografia em coluna de flash usando 0-10% de acetato de etila como eluente forneceu (E)-1-bromo-3-flúor-2-metóxi-5-(4-metoxistiril)benzeno como um sólido branco (0,48 g, 20%): pf 78,0-84,8°C; 1H RMN (400 MHz, CDCh) δ 7,47 (d, J = 8,7 Hz, 2H), 7,39 (d, J = 12,5 Hz, 1H), 7,19 (dd, J = 16,1, 1,7 Hz, 1H), 7,14 (d, J = 8,1 Hz, 1H), 6,94 - 6,89 (m, 2H), 6,86 (d, J = 16,2 Hz, 1H), 3,90 (s, 3H), 3,84 (s, 3H); 19F RMN (376 MHz, CDCl3) δ -135,86; EIMS m/z 336,0.Exemplo 53: Preparação de (E)-3-cloro-5-(4-metoxiestiril)benzaldeído (C146)

Figure img0299
[000392] To a stirred solution of diethyl(4-methoxybenzyl)phosphonate (1.85 ml, 8.14 mmol) in N,N-dimethylformamide (9 ml) at 0°C was added a solution of sodium methoxide ( 5.4M in methanol, 1.38ml, 7.47mmol). 3-Bromo-4,5-fluorobenzaldehyde (1.5 g, 6.79 mmol) in N,N-dimethylformamide (3 mL) was added and the reaction mixture was heated at 65°C for 2 hours. The reaction mixture was allowed to cool to room temperature and was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by flash column chromatography using 0-10% ethyl acetate as eluent provided (E)-1-bromo-3-fluoro-2-methoxy-5-(4-methoxystyryl)benzene as a white solid (0, 48 g, 20%): mp 78.0-84.8°C; 1H NMR (400 MHz, CDCh) δ 7.47 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 12.5 Hz, 1H), 7.19 (dd, J = 16 .1, 1.7 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.94 - 6.89 (m, 2H), 6.86 (d, J = 16, 2Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H); 19F NMR (376 MHz, CDCl 3 ) δ -135.86; EIMS m/z 336.0.Example 53: Preparation of (E)-3-chloro-5-(4-methoxystyryl)benzaldehyde (C146)
Figure img0299

[000393] A uma solução agitada de 3-bromo-5-clorobenzaldeído (20,0 g, 91,32 mmol) em dimetilacetamida, 1-metóxi-4-vinilbenzeno (18,3 g, 136,9 mmol) e trietilamina (50,5 mL, 273,96 mmol) foram adicionados e a mistura de reação foi desgaseificada com argônio por 5 minutos. Acetato de paládio(II) (410 mg, 1,83 mmol) e tri-o-tolilfosfina (1,11 g, 3,65 mmol) foram adicionados e a mistura de reação resultante foi aquecida a 100°C por 16 horas. A mistura de reação foi vertida em água e extraída com acetato de etila. A camada orgânica combinada foi seca sobre sulfato de sódio e concentrada sob pressão redu- zida. O material bruto resultante foi purificado por cromatografia flash em coluna usando acetato de etila em éter de petróleo a 5-10% como o eluente para resultar no composto do título como um sólido amarelo (13,5 g, 54%): 1H RMN (300 MHz, CDCl3) δ 9,99 (s, 1H), 7,85 (s, 1H), 7,69 (s, 2H), 7,47 (d, J = 8,4 Hz, 2H), 7,16 (d, J = 16,2 Hz, 1H), 6,94 (t, J = 8,4 Hz, 3H), 3,84 (s, 3H); ESIMS m/z 273 ([M+H]+).[000393] To a stirred solution of 3-bromo-5-chlorobenzaldehyde (20.0 g, 91.32 mmol) in dimethylacetamide, 1-methoxy-4-vinylbenzene (18.3 g, 136.9 mmol) and triethylamine ( 50.5 mL, 273.96 mmol) were added and the reaction mixture was degassed with argon for 5 minutes. Palladium(II) acetate (410 mg, 1.83 mmol) and tri-o-tolylphosphine (1.11 g, 3.65 mmol) were added and the resulting reaction mixture was heated at 100°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using ethyl acetate in 5-10% petroleum ether as the eluent to give the title compound as a yellow solid (13.5 g, 54%):1H NMR ( 300 MHz, CDCl 3 ) δ 9.99 (s, 1H), 7.85 (s, 1H), 7.69 (s, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7 .16 (d, J = 16.2 Hz, 1H), 6.94 (t, J = 8.4 Hz, 3H), 3.84 (s, 3H); ESIMS m/z 273 ([M+H]+).

[000394] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 53:(E)-2-Cloro-5-(4-metoxiestiril)benzaldeído (C147)

Figure img0300
[000394] The following compounds were prepared in a manner similar to the procedure described in Example 53: (E)-2-Chloro-5-(4-methoxystyryl)benzaldehyde (C147)
Figure img0300

[000395] Isolado como um sólido amarelo pálido (11,8 g, 27%): 1H RMN (300 MHz, CDCl3) δ 10,45 (s, 1H), 8,02 (s, 1H), 7,62 (d, J = 6,4 Hz, 1H), 7,46 - 7,40 (m, 3H), 7,12 (d, J = 16,4 Hz, 1H), 6,95 - 6,90 (m, 3H), 3,95 (s, 3H); ESIMS m/z 273 ([M+H]+).(E)-3-Flúor-5-(4-metoxiestiril)benzaldeído (C148)

Figure img0301
[000395] Isolated as a pale yellow solid (11.8 g, 27%): 1H NMR (300 MHz, CDCl 3 ) δ 10.45 (s, 1H), 8.02 (s, 1H), 7.62 ( d, J = 6.4 Hz, 1H), 7.46 - 7.40 (m, 3H), 7.12 (d, J = 16.4 Hz, 1H), 6.95 - 6.90 (m , 3H), 3.95 (s, 3H); ESIMS m/z 273 ([M+H]+).(E)-3-Fluor-5-(4-methoxystyryl)benzaldehyde (C148)
Figure img0301

[000396] Isolado como um sólido amarelo pálido (25 g, 57%): 1H RMN (300 MHz, CDCl3) δ 10 (s, 1H), 7,77 (s, 1H), 7,48 - 7,40 (m, 4H), 7,16 (d, J = 16,2 Hz, 1H), 6,94 (t, J = 15,6 Hz, 3H), 3,84 (s, 3H); ESIMS m/z 275 ([M+H]+).(E)-2-Flúor-5-(4-metoxiestiril)benzaldeído (C149)

Figure img0302
[000396] Isolated as a pale yellow solid (25 g, 57%): 1H NMR (300 MHz, CDCl 3 ) δ 10 (s, 1H), 7.77 (s, 1H), 7.48 - 7.40 ( m, 4H), 7.16 (d, J = 16.2 Hz, 1H), 6.94 (t, J = 15.6 Hz, 3H), 3.84 (s, 3H); ESIMS m/z 275 ([M+H]+).(E)-2-Fluor-5-(4-methoxystyryl)benzaldehyde (C149)
Figure img0302

[000397] Isolado como um sólido esbranquiçado (0,25 g, 20%): 1H RMN (400 MHz, CDCl3) δ 10,43 (s, 1H), 7,90 (d, J = 8,4 Hz, 1H), 7,54 - 7,46 (m, 4H), 7,20 (d, J = 16,0 Hz, 1H), 6,94 - 6,90 (m, 3H), 3,85 (s, 3H); ESIMS m/z 274 ([M+H]+).(E)-2-Cloro-4-(4-metoxiestiril)benzaldeído (C150)

Figure img0303
[000397] Isolated as an off-white solid (0.25 g, 20%): 1H NMR (400 MHz, CDCl 3 ) δ 10.43 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H ), 7.54 - 7.46 (m, 4H), 7.20 (d, J = 16.0 Hz, 1H), 6.94 - 6.90 (m, 3H), 3.85 (s, 3H); ESIMS m/z 274 ([M+H]+).(E)-2-Chloro-4-(4-methoxystyryl)benzaldehyde (C150)
Figure img0303

[000398] Isolado como um sólido esbranquiçado (8,0 g, 57%): 1H RMN (400 MHz, CDCl3) δ 10,41 (s, 1H), 7,97 (dd, J = 2,4, 6,8 Hz, 1H), 7,71 - 7,67 (m, 1H), 7,44 (d, J = 8,0 Hz, 2H), 7,18 - 7,13 (m, 1H), 7,08 - 7,04 (m, 1H), 6,95 - 6,90 (m, 3H), 3,85 (s, 3H); ESIMS m/z 257 ([M+H]+).(E)-2-Flúor-4-(4-metoxiestiril)benzaldeído (C151)

Figure img0304
[000398] Isolated as an off-white solid (8.0 g, 57%): 1H NMR (400 MHz, CDCl 3 ) δ 10.41 (s, 1H), 7.97 (dd, J = 2.4, 6, 8 Hz, 1H), 7.71 - 7.67 (m, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.18 - 7.13 (m, 1H), 7. 08 - 7.04 (m, 1H), 6.95 - 6.90 (m, 3H), 3.85 (s, 3H); ESIMS m/z 257 ([M+H]+).(E)-2-Fluor-4-(4-methoxystyryl)benzaldehyde (C151)
Figure img0304

[000399] Isolado como um sólido marrom (15 g, 78%): 1H RMN (400 MHz, CDCl3) δ 10,35 (s, 1H), 7,83 (t, J = 7,6 Hz, 1H), 7,48 (d, J = 8,8 Hz, 2H), 7,35 (d, J = 8,4 Hz, 1H), 7,23 - 7,18 (m, 2H), 6,96 - 6,91 (m, 3H), 3,95 (s, 3H); 19F RMN (376 MHz, CDCl3) δ -122,26; ESIMS m/z 257 ([M+H]+).(E)-3-(4-Metoxiestiril)benzaldeído (C152)

Figure img0305
[000399] Isolated as a brown solid (15 g, 78%): 1H NMR (400 MHz, CDCl 3 ) δ 10.35 (s, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.23 - 7.18 (m, 2H), 6.96 - 6 .91 (m, 3H), 3.95 (s, 3H); 19F NMR (376 MHz, CDCl 3 ) δ -122.26; ESIMS m/z 257 ([M+H]+).(E)-3-(4-Methoxystyril)benzaldehyde (C152)
Figure img0305

[000400] Isolado como um sólido marrom (18 g, 46%): 1H RMN (400 MHz, CDCl3) δ 10,15 (s, 1H), 8,00 (s, 1H), 7,73 (d, J = 7,2 Hz, 2H), 7,53 - 7,46 (m, 3H), 7,17 (d, J = 16,8 Hz, 1H), 7,01 (d, J = 16,0 Hz, 1H), 6,92 (d, J = 8,8 Hz, 2H), 3,84(s, 3H); ESIMS m/z 239 ([M+H]+).(E)-4-(4-Metoxiestiril)benzaldeído (C153)

Figure img0306
[000400] Isolated as a brown solid (18 g, 46%): 1H NMR (400 MHz, CDCl 3 ) δ 10.15 (s, 1H), 8.00 (s, 1H), 7.73 (d, J = 7.2 Hz, 2H), 7.53 - 7.46 (m, 3H), 7.17 (d, J = 16.8 Hz, 1H), 7.01 (d, J = 16.0 Hz , 1H), 6.92 (d, J = 8.8 Hz, 2H), 3.84(s, 3H); ESIMS m/z 239 ([M+H]+).(E)-4-(4-Methoxystyril)benzaldehyde (C153)
Figure img0306

[000401] Isolado como um sólido marrom claro (9,0 g, 47%): 1H RMN (400 MHz, CDCl3) δ 10 (s, 1H), 7,84 (d, J = 8,0 Hz, 2H), 7,61 (d, J = 7,6 Hz, 2H), 7,48 (d, J = 8,0 Hz, 2H), 7,23 (t, J = 7,6 Hz, 1H), 7,00 (d, J = 16,0 Hz, 1H), 6,92 (d, J = 8,8 Hz, 2H), 3,84 (s, 3H).Exemplo 54: Preparação de (E)-1-cloro-3-(difluorometil)-5-(4-metóxi- estiril)benzeno (C154)

Figure img0307
[000401] Isolated as a light brown solid (9.0 g, 47%): 1H NMR (400 MHz, CDCl3) δ 10 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H) , 7.61 (d, J = 7.6 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7 .00 (d, J = 16.0 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H). Example 54: Preparation of (E)-1 -chloro-3-(difluoromethyl)-5-(4-methoxystyryl)benzene (C154)
Figure img0307

[000402] A uma solução agitada de (E)-3-cloro-5-(4-metoxiestiril) benzaldeído (C146)(13 g, 47,79 mmol) em diclorometano (130 mL) foi adicionado trifluoreto de dietilaminoenxofre (31,5 mL, 238,97 mmol) a - 78°C. A solução resultante foi agitada por 20 horas à temperatura am-biente. A mistura de reação foi resfriada a 0°C e uma solução de bi-carbonato de sódio aquoso saturado foi adicionada gota a gota. As camadas foram separadas e a camada aquosa foi extraída com diclo- rometano (3 x 75 mL). A camada orgânica combinada foi lavada com água e solução salina, seca sobre sulfato de sódio e concentrada. O material bruto foi purificado por cromatografia flash em coluna usando acetato de etila em hexanos a 10-20% como o eluente para resultar no composto do título como um óleo amarelo pálido (13,1 g, 94%): 1H RMN (400 MHz, CDCl3) δ 7,55 (s, 1H), 7,45 (d, J = 8,8 Hz, 3H), 7,34 (s, 1H), 7,10 (d, J = 16 Hz, 1H), 6,90 (t, J = 8,4 Hz, 3H), 6,61 (t, J = 56,4 Hz, 1H), 3,80 (s, 3H); 19F RMN (376 MHz, CDCl3) δ -111,72.[000402] To a stirred solution of (E)-3-chloro-5-(4-methoxystyryl)benzaldehyde (C146)(13 g, 47.79 mmol) in dichloromethane (130 mL) was added diethylaminosulfur trifluoride (31, 5 ml, 238.97 mmol) at -78°C. The resulting solution was stirred for 20 hours at room temperature. The reaction mixture was cooled to 0°C and a saturated aqueous sodium bicarbonate solution was added dropwise. The layers were separated and the aqueous layer was extracted with dichloromethane (3x75ml). The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude material was purified by flash column chromatography using 10-20% ethyl acetate in hexanes as the eluent to give the title compound as a pale yellow oil (13.1 g, 94%):1H NMR (400 MHz , CDCl 3 ) δ 7.55 (s, 1H), 7.45 (d, J = 8.8 Hz, 3H), 7.34 (s, 1H), 7.10 (d, J = 16 Hz, 1H ), 6.90 (t, J = 8.4 Hz, 3H), 6.61 (t, J = 56.4 Hz, 1H), 3.80 (s, 3H); 19F NMR (376 MHz, CDCl 3 ) δ -111.72.

[000403] Os seguintes compostos foram preparados de maneira se- melhante ao procedimento descrito no Exemplo 54: (E)-1-Cloro-2-(difluorometil)-4-(4-metoxiestiril)benzeno (C155)

Figure img0308
[000403] The following compounds were prepared in a manner similar to the procedure described in Example 54: (E)-1-Chloro-2-(difluoromethyl)-4-(4-methoxystyryl)benzene (C155)
Figure img0308

[000404] Isolado como um sólido esbranquiçado (12 g, 94%): 1H RMN (300 MHz, CDCI3) δ 7,75 (s, 1H), 7,51 - 7,44 (m, 3H), 7,37 (d, J = 8,4 Hz, 1H), 7,13 (d, J = 6,6 Hz, 1H), 7,06 (s, 1H), 6,95 - 6,89 (m, 3H), 3,95(s, 3H); 19F RMN (282 MHz, CDCl3) δ -115,31; ESIMS m/z 295 ([M+H]+).(E)-1-(Difluorometil)-3-flúor-5-(4-metoxiestiril)benzeno (C156)

Figure img0309
[000404] Isolated as an off-white solid (12 g, 94%): 1H NMR (300 MHz, CDCl 3 ) δ 7.75 (s, 1H), 7.51 - 7.44 (m, 3H), 7.37 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 6.6 Hz, 1H), 7.06 (s, 1H), 6.95 - 6.89 (m, 3H) , 3.95(s, 3H); 19F NMR (282 MHz, CDCl 3 ) δ -115.31; ESIMS m/z 295 ([M+H]+).(E)-1-(Difluoromethyl)-3-fluoro-5-(4-methoxystyryl)benzene (C156)
Figure img0309

[000405] Isolado como um sólido esbranquiçado (20 g, 75%); 1H RMN (300 MHz, CDCl3) δ 7,46 (d, J = 8,0 Hz, 2H), 7,38 (s, 1H), 7,28 (s, 1H), 7,08 (t, J = 16,2 Hz, 2H), 6,92 (t, J = 15,6 Hz, 3H), 6,63 (t, J = 56,0 Hz, 1H), 3,84 (s, 3H); ESIMS m/z 279 ([M+H]+).(E)-2-(Difluorometil)-1-flúor-4-(4-metoxiestiril)benzeno (C157)

Figure img0310
[000405] Isolated as an off-white solid (20 g, 75%); 1H NMR (300 MHz, CDCl 3 ) δ 7.46 (d, J = 8.0 Hz, 2H), 7.38 (s, 1H), 7.28 (s, 1H), 7.08 (t, J = 16.2 Hz, 2H), 6.92 (t, J = 15.6 Hz, 3H), 6.63 (t, J = 56.0 Hz, 1H), 3.84 (s, 3H); ESIMS m/z 279 ([M+H]+).(E)-2-(Difluoromethyl)-1-fluor-4-(4-methoxystyryl)benzene (C157)
Figure img0310

[000406] Isolado como um sólido esbranquiçado (14,0 g, 70%): 1H RMN (300 MHz, CDCI3) δ 7,69 (d, J = 9,0 Hz, 1H), 7,57 - 7,53 (m, 1H), 7,45 (d, J = 9,9 Hz, 2H), 7,13 - 7,06 (m, 2H), 7,00 - 6,89 (m, 4H), 3,85 (s, 3H); ESIMS m/z 279 ([M+H]+).(E)-2-Cloro-1-(difluorometil)-4-(4-metoxiestiril)benzeno (C158)

Figure img0311
[000406] Isolated as an off-white solid (14.0 g, 70%): 1H NMR (300 MHz, CDCl 3 ) δ 7.69 (d, J = 9.0 Hz, 1H), 7.57 - 7.53 (m, 1H), 7.45 (d, J = 9.9 Hz, 2H), 7.13 - 7.06 (m, 2H), 7.00 - 6.89 (m, 4H), 3. 85 (s, 3H); ESIMS m/z 279 ([M+H]+).(E)-2-Chloro-1-(difluoromethyl)-4-(4-methoxystyryl)benzene (C158)
Figure img0311

[000407] Isolado como um sólido esbranquiçado (18,0 g, 90%): 1H RMN (400 MHz, CDCl3) δ 7,61 (d, J = 8,0 Hz, 1H), 7,51 (s, 1H), 7,47 - 7,43 (m, 3H), 7,14 - 7,07 (m, 1H), 6,94 - 6,80 (m, 4H), 3,85(s, 3H); ESIMS m/z 294 ([M+H]+).(E)-1-(Difluorometil)-2-flúor-4-(4-metoxiestiril)benzeno (C159)

Figure img0312
[000407] Isolated as an off-white solid (18.0 g, 90%): 1H NMR (400 MHz, CDCl 3 ) δ 7.61 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H) ), 7.47 - 7.43 (m, 3H), 7.14 - 7.07 (m, 1H), 6.94 - 6.80 (m, 4H), 3.85(s, 3H); ESIMS m/z 294 ([M+H]+).(E)-1-(Difluoromethyl)-2-fluoro-4-(4-methoxystyryl)benzene (C159)
Figure img0312

[000408] Isolado como um sólido amarelo pálido (9 g, 55%): 1H RMN (400 MHz, CDCl3) δ 7,54 (t, J = 8,0 Hz, 1H), 7,46 (d, J = 8,8 Hz, 2H), 7,32 (d, J = 8,0 Hz, 1H), 7,22 (d, J = 11,6 Hz, 1H), 7,11 (d, J = 16,4 Hz, 1H), 7,01 - 6,83 (m, 4H), 3,95 (s, 3H); 19F RMN (376 MHz, CDCl3) δ - 113,57, -114,25, -120,33; ESIMS m/z 279 ([M+H]+).(E)-1-(Difluorometil)-3-(4-metoxiestiril)benzeno (C160)

Figure img0313
[000408] Isolated as a pale yellow solid (9 g, 55%): 1H NMR (400 MHz, CDCl 3 ) δ 7.54 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 11.6 Hz, 1H), 7.11 (d, J = 16, 4Hz, 1H), 7.01 - 6.83 (m, 4H), 3.95 (s, 3H); 19F NMR (376 MHz, CDCl 3 ) δ - 113.57, -114.25, -120.33; ESIMS m/z 279 ([M+H]+).(E)-1-(Difluoromethyl)-3-(4-methoxystyryl)benzene (C160)
Figure img0313

[000409] Isolado como um sólido amarelo pálido (6 g, 68%): 1H RMN (300 MHz, CDCl3) δ 7,62 - 7,56 (m, 2H), 7,48 - 7,34 (m, 4H), 7,11 (d, J = 16,5 Hz, 1H), 7,00 (s, 1H), 6,95 - 6,89 (t, 2H), 6,66 (t, 1H), 3,95 (s, 3H); 19F RMN (282 MHz, CDCl3) δ -110,84; ESIMS m/z 261 ([M+H]+).(E)-1-(Difluorometil)-4-(4-metoxiestiril)benzeno (C161)

Figure img0314
[000409] Isolated as a pale yellow solid (6 g, 68%): 1H NMR (300 MHz, CDCl 3 ) δ 7.62 - 7.56 (m, 2H), 7.48 - 7.34 (m, 4H) ), 7.11 (d, J = 16.5 Hz, 1H), 7.00 (s, 1H), 6.95 - 6.89 (t, 2H), 6.66 (t, 1H), 3 .95 (s, 3H); 19F NMR (282 MHz, CDCl 3 ) δ -110.84; ESIMS m/z 261 ([M+H]+).(E)-1-(Difluoromethyl)-4-(4-methoxystyryl)benzene (C161)
Figure img0314

[000410] Isolado como um sólido esbranquiçado (15,4 g, 75%): 1H RMN (300 MHz, CDCI3) δ 7,57 - 7,45 (m, 6H), 7,12 (d, J = 15,9 Hz, 1H), 7,00 - 6,89 (m, 3H), 6,64 (t, J = 57 Hz, 1H), 3,92 (s, 3H); ESIMS m/z 260,17 ([M+H]+).Exemplo 55: Preparação de cloridrato de 3-aminociclobutan-1-ona (C162)

Figure img0315
CIH3N._[000410] Isolated as an off-white solid (15.4 g, 75%): 1H NMR (300 MHz, CDCl 3 ) δ 7.57 - 7.45 (m, 6H), 7.12 (d, J = 15, 9Hz, 1H), 7.00 - 6.89 (m, 3H), 6.64 (t, J = 57Hz, 1H), 3.92 (s, 3H); ESIMS m/z 260.17 ([M+H]+). Example 55: Preparation of 3-aminocyclobutan-1-one hydrochloride (C162)
Figure img0315
CIH3N._

[000411] A uma solução de terc-butil (3-oxociclobutil)carbamato (1,0 g, 5,1 mmol) em diclorometano (34 mL) a 23°C foi adicionada 4 M de solução de ácido clorídrico em 1,4-dioxano (6,4 mL, 26 mmol). A mistura de reação foi agitada a 23°C por 24 horas. A mistura de reação foi concentrada para fornecer o composto do título como um pó esbran-quiçado (0,620 g, 100%): 1H RMN (400 MHz, DMSO-d6) δ 8,55 (br s, 3H), 3,92 (m, 1H), 3,44 - 3,34 (m, 2H), 3,32 - 3,22 (m, 2H).Exemplo 56: Preparação de 2-cloro-N-((2,2-difluorociclopropil)-5-nitro- benzamida (C163)

Figure img0316
[000411] To a solution of tert-butyl (3-oxocyclobutyl)carbamate (1.0 g, 5.1 mmol) in dichloromethane (34 mL) at 23°C was added 4 M hydrochloric acid solution in 1.4 -dioxane (6.4 mL, 26 mmol). The reaction mixture was stirred at 23°C for 24 hours. The reaction mixture was concentrated to furnish the title compound as an off-white powder (0.620 g, 100%): 1H NMR (400 MHz, DMSO-d6) δ 8.55 (br s, 3H), 3.92 (m, 1H), 3.44 - 3.34 (m, 2H), 3.32 - 3.22 (m, 2H). Example 56: Preparation of 2-chloro-N-((2,2-difluorocyclopropyl) )-5-nitro-benzamide (C163)
Figure img0316

[000412] A uma solução de ácido 2-cloro-5-nitrobenzoico (0,2 g, 0,992 mmol) em diclorometano seco (4 mL) resfriado em um banho- maria gelado foi adicionada 1 gota de N,N-dimetilformamida, seguido por cloreto de oxalila (0,130 mL, 1,488 mmol). A reação foi aquecida em temperatura e agitada por 30 min. Separadamente, cloridrato de 2,2-difluorociclopropanamina (0,257 g, 1,984 mmol) e trietilamina (0,691 mL, 4,96 mmol) foram umedecidos em diclorometano (4 mL). A pasta líquida foi resfriada em um banho-maria gelado e a solução de cloreto ácido foi adicionada lentamente. A mistura resultante foi aquecida em temperatura ambiente durante a noite. A reação foi concentrada em pressão reduzida e o resíduo foi dividido entre acetato de eti- la e ácido clorídrico (1 N). As fases foram cortadas e a camada orgânica foi lavada com ácido clorídrico (1 N) seguido de solução de bicarbonato de sódio aquoso saturado e, em seguida, salmoura. A camada orgânica foi concentrada e o resíduo foi purificado por cromatografia em coluna usando 0-30% de acetato de etila/hexanos para obter o composto do título como um sólido branco (0,058 g, 21%): 1H RMN (400 MHz, CDCl3) δ 8,57 (d, J = 2,7 Hz, 1H), 8,26 (dd, J = 8,8, 2,8 Hz, 1H), 7,63 (d, J = 8,8 Hz, 1H), 6,53 (s, 1H), 3,70 - 3,52 (m, 1H), 2,05 - 1,91 (m, 1H), 1,62 - 1,48 (m, 1H); IR (película fina) 3268, 1661, 1538 cm-1; ESIMS m/z 277 ([M+H]+).Exemplo 57: Preparação de ácido (1R,3R)-2,2-dicloro-3-(3,5-dicloro- fenil)-ciclopropano-1-carboxílico (C164)

Figure img0317
[000412] To a solution of 2-chloro-5-nitrobenzoic acid (0.2 g, 0.992 mmol) in dry dichloromethane (4 mL) cooled in an ice-water bath was added 1 drop of N,N-dimethylformamide, followed by oxalyl chloride (0.130 mL, 1.488 mmol). The reaction was warmed to temperature and stirred for 30 min. Separately, 2,2-difluorocyclopropanamine hydrochloride (0.257 g, 1.984 mmol) and triethylamine (0.691 mL, 4.96 mmol) were moistened in dichloromethane (4 mL). The slurry was cooled in an ice-cold water bath and the acid chloride solution was added slowly. The resulting mixture was warmed to room temperature overnight. The reaction was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and hydrochloric acid (1N). The phases were cut and the organic layer was washed with hydrochloric acid (1N) followed by saturated aqueous sodium bicarbonate solution and then brine. The organic layer was concentrated and the residue was purified by column chromatography using 0-30% ethyl acetate/hexanes to obtain the title compound as a white solid (0.058 g, 21%): 1H NMR (400 MHz, CDCl 3 ) ) δ 8.57 (d, J = 2.7 Hz, 1H), 8.26 (dd, J = 8.8, 2.8 Hz, 1H), 7.63 (d, J = 8.8 Hz , 1H), 6.53 (s, 1H), 3.70 - 3.52 (m, 1H), 2.05 - 1.91 (m, 1H), 1.62 - 1.48 (m, 1H ); IR (thin film) 3268, 1661, 1538 cm-1; ESIMS m/z 277 ([M+H]+).Example 57: Preparation of (1R,3R)-2,2-dichloro-3-(3,5-dichloro-phenyl)-cyclopropane-1-carboxylic acid ( C164)
Figure img0317

[000413] 1a resolução: (R)-1-Feniletanamina (6,49 g, 53,0 mmol) foi adicionado lentamente a uma solução agitada de ácido rac-2,2-dicloro- 3-(3,5-diclorofenil)ciclopropano-carboxílico) (32,45 g, 106 mmol) em acetona (106 mL). A solução resultante foi agitada a 45°C. Após um sólido começar a se depositar, a mistura foi colocada a 5°C durante 4 horas. O sólido foi coletado, lavado com acetona fria mínima e seco. O sal sólido branco foi diluído com acetato de etila (100 mL) e lavado com ácido clorídrico aquoso (1 N, 10 mL) e solução salina (30 mL). A camada orgânica foi seca com sulfato de sódio, filtrada e concentrada para gerar o produto do título como um sólido branco (10,33 g, 88% de excesso enantiomérico "ee").[000413] 1st resolution: (R)-1-Phenylethanamine (6.49 g, 53.0 mmol) was added slowly to a stirred solution of rac-2,2-dichloro-3-(3,5-dichlorophenyl) acid cyclopropane-carboxylic acid) (32.45 g, 106 mmol) in acetone (106 mL). The resulting solution was stirred at 45°C. After a solid began to settle, the mixture was placed at 5°C for 4 hours. The solid was collected, washed with minimal cold acetone and dried. The white solid salt was diluted with ethyl acetate (100ml) and washed with aqueous hydrochloric acid (1N, 10ml) and brine (30ml). The organic layer was dried with sodium sulfate, filtered and concentrated to give the title product as a white solid (10.33 g, 88% enantiomeric excess "ee").

[000414] 2a resolução: (R)-1-Feniletanamina (3,4 g, 28 mmol) foi len-tamente adicionado a uma solução agitada de ácido rac-2,2-dicloro-3- (3,5-diclorofenil)ciclopropano-carboxílico) (10,33 g, 88% ee) em acetona (100 mL). Após 2 horas, o sódico foi coletado, lavado com acetona fria mínima e seco. O sólido foi tratado com ácido clorídrico aquoso para proporcionar o composto de título como um sólido branco (7,84 g, 97% ee, 24,2%): Rotação Específica: +47,4 (10 mg/mL em acetonitrila, 589 nm, 25,2°C); 1H RMN (300 MHz, CDCl3) δ 7,36 (t, J = 1,9 Hz, 1H), 7,17 (dd, J = 1,9, 0,7 Hz, 2H), 3,48 - 3,37 (m, 1H), 2,87 (d, J = 8,3 Hz, 1H); 13C RMN (400 MHz, DMSO-d6) δ 166,28, 136,40, 133,39, 127,27, 127,04, 61,36, 37,10, 35,98; ESIMS m/z 298,9 ([M-H]-).[000414] 2nd resolution: (R)-1-Phenylethanamine (3.4 g, 28 mmol) was slowly added to a stirred solution of rac-2,2-dichloro-3-(3,5-dichlorophenyl) acid cyclopropane carboxylic) (10.33 g, 88% ee) in acetone (100 mL). After 2 hours the sodium was collected, washed with minimal cold acetone and dried. The solid was treated with aqueous hydrochloric acid to provide the title compound as a white solid (7.84 g, 97% ee, 24.2%): Specific Rotation: +47.4 (10 mg/ml in acetonitrile, 589 nm, 25.2°C); 1H NMR (300 MHz, CDCl3) δ 7.36 (t, J = 1.9 Hz, 1H), 7.17 (dd, J = 1.9, 0.7 Hz, 2H), 3.48 - 3 .37 (m, 1H), 2.87 (d, J = 8.3 Hz, 1H); 13 C NMR (400 MHz, DMSO-d6) δ 166.28, 136.40, 133.39, 127.27, 127.04, 61.36, 37.10, 35.98; ESIMS m/z 298.9 ([M-H]-).

[000415] ee foi determinado por método de HPLC Quiral conforme se segue: Coluna: CHIRALPAK@ ZWIX(+), tamanho de partícula de 3 μm, dimensão de 3 mm x 150 mmL, DAIC 511584; Fase móvel: 49% de acetonitrila/49% de metanol/água com ácido fórmico a 50 mM e dieti- lamina; Vazão: 0,5 mL/min; Tempo: 9 min; Temperatura: 25°C[000415] ee was determined by Chiral HPLC method as follows: Column: CHIRALPAK™ ZWIX(+), particle size 3 µm, dimension 3 mm x 150 mmL, DAIC 511584; Mobile phase: 49% acetonitrile/49% methanol/water with 50 mM formic acid and diethylamine; Flow: 0.5 mL/min; Time: 9 min; Temperature: 25°C

[000416] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 57:Ácido (1 R,3R)-2,2-dicloro-3-(3,4-diclorofenil)ciclopropano-1-carboxílico (C165)

Figure img0318
[000416] The following compounds were prepared in a manner similar to the procedure described in Example 57: (1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxylic acid (C165 )
Figure img0318

[000417] Isolado como um sólido branco (6,7 g, 30%, 96% ee). Da- dos analíticos são consistentes com ácido racêmico C3.Ácido (1 R,3R)-2,2-dicloro-3-(3-cloro-4-fluorofenil)ciclopropano-1 -carbo-xílico (C166)

Figure img0319
[000417] Isolated as a white solid (6.7 g, 30%, 96% ee). Analytical data are consistent with racemic acid C3.(1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxylic acid (C166)
Figure img0319

[000418] Isolado como um sólido branco (0,5 g, 13%, 99% ee). Dados analíticos são consistentes com ácido racêmico C16.Ácido (1 R,3R)-2,2-dicloro-3-(3,4,5-triclorofenil)ciclopropano-1-carboxí- lico (C167)

Figure img0320
[000418] Isolated as a white solid (0.5 g, 13%, 99% ee). Analytical data are consistent with racemic acid C16.(1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxylic acid (C167)
Figure img0320

[000419] Isolado como um sólido branco (2 g, 29%, 99% ee). Dados analíticos são consistentes com ácido racêmico C2.Exemplo 58: Ácido (1S,3S)-2,2-Dicloro-3-(3,5-diclorofenil)-ciclopropano-1-carboxílico (C168)

Figure img0321
[000419] Isolated as a white solid (2 g, 29%, 99% ee). Analytical data are consistent with racemic acid C2.Example 58: (1S,3S)-2,2-Dichloro-3-(3,5-dichlorophenyl)-cyclopropane-1-carboxylic acid (C168)
Figure img0321

[000420] O licor mãe da 1° resolução de ácido R,R (do Exemplo 33) foi concentrado e dissolvido em acetona (~100 mL) e aquecido a 45°C. Com redemoinho, (S)-1-feniletanamina (5,0 g, 41,2 mmol, 0,8 eq) foi adicionada. A solução resultante foi agitada a 45°C. Após um sólido começar a se depositar, a mistura foi colocada a 5°C durante 2 horas. O sólido foi coletado, lavado com acetona fria mínima e seco a vácuo a 35°C. O sólido foi tratado com HCl (aq) para fornecer o ácido S,S livre como um sólido branco (9,87 g, 85% ee, 59% de rendimento). Uma segunda resolução do ácido S,S combinado com ee a 85% (13,45 g, 41,7 mmol, 85% ee) usando o mesmo procedimento com (S)- 1-feniletanamina (3,8 g, 31,3 mmol, 0,75 eq) forneceu o ácido S,S com um sólido branco (8,53 g, 99% ee, 26% de rendimento). Rotação Específica: -51,9 (10 mg/mL em ACN, 589 nm, 25,2°C). Dados analíticos são consistentes com ácido racêmico C1.[000420] The mother liquor of the 1st resolution of acid R,R (from Example 33) was concentrated and dissolved in acetone (~100 ml) and heated to 45°C. With swirl, (S)-1-phenylethanamine (5.0 g, 41.2 mmol, 0.8 eq) was added. The resulting solution was stirred at 45°C. After a solid began to settle, the mixture was placed at 5°C for 2 hours. The solid was collected, washed with minimal cold acetone and vacuum dried at 35°C. The solid was treated with HCl (aq) to provide the free S,S acid as a white solid (9.87 g, 85% ee, 59% yield). A second resolution of the combined S,S acid with 85% ee (13.45 g, 41.7 mmol, 85% ee) using the same procedure with (S)-1-phenylethanamine (3.8 g, 31.3 mmol, 0.75 eq) provided the S,S acid as a white solid (8.53 g, 99% ee, 26% yield). Specific Rotation: -51.9 (10 mg/ml in ACN, 589 nm, 25.2°C). Analytical data are consistent with C1 racemic acid.

[000421] ee foi determinado por método de HPLC Quiral conforme se segue: Coluna: CHIRALPAK@ ZWIX(+), tamanho de partícula de 3 μm, dimensão de 3 mm x 150 mmL, DAIC 511584; Fase móvel: 49% de acetonitrila/49% de metanol/água com ácido fórmico a 50 mM e dieti- lamina; Vazão: 0,5 mL/min; Tempo: 9 min; Temperatura: 25°C[000421] ee was determined by Chiral HPLC method as follows: Column: CHIRALPAK™ ZWIX(+), particle size 3 µm, dimension 3 mm x 150 mmL, DAIC 511584; Mobile phase: 49% acetonitrile/49% methanol/water with 50 mM formic acid and diethylamine; Flow: 0.5 mL/min; Time: 9 min; Temperature: 25°C

[000422] Os seguintes compostos foram preparados de maneira se-melhante ao procedimento descrito no Exemplo 58:Ácido (1 S,3S)-2,2-Dicloro-3-(3,4-diclorofenil)ciclopropano-1-carboxílico (C169)

Figure img0322
[000422] The following compounds were prepared in a manner similar to the procedure described in Example 58: (1S,3S)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxylic acid (C169 )
Figure img0322

[000423] Isolado como um sólido branco (7 g, 35%, 98% ee). Dados analíticos são consistentes com ácido racêmico C3.Ácido (1 S,3S)-2,2-Dicloro-3-(3-cloro-4-fluorofenil)ciclopropano-1 -carbo- xílico (C170)

Figure img0323
[000423] Isolated as a white solid (7 g, 35%, 98% ee). Analytical data are consistent with racemic acid C3.(1S,3S)-2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxylic acid (C170)
Figure img0323

[000424] Isolado como um sólido branco (0,64 g, 27%, 98% ee). Dados analíticos são consistentes com ácido racêmico C16. Ácido (1 S,3S)-2,2-Dicloro-3-(3,4,5-triclorofenil)ciclopropano-1-carboxí- lico (C171)

Figure img0324
[000424] Isolated as a white solid (0.64 g, 27%, 98% ee). Analytical data are consistent with C16 racemic acid. (1S,3S)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxylic acid (C171)
Figure img0324

[000425] Isolado como um sólido branco (0,75 g, 41%, 99% ee). Dados analíticos são consistentes com ácido racêmico C2.[000425] Isolated as a white solid (0.75 g, 41%, 99% ee). Analytical data are consistent with C2 racemic acid.

[000426] É reconhecido que alguns reagentes e condições de reação podem não ser compatíveis com determinadas funcionalidades que podem estar presentes em determinadas moléculas da Fórmula Um e determinadas moléculas usadas na preparação de determinadas mo-léculas da Fórmula Um. Nesses casos, pode ser necessário usar pro-teção padrão e protocolos de desproteção amplamente relatados na literatura e bem conhecidos para um versado na técnica. Além disso, em alguns casos, pode ser necessário realizar etapas sintéticas de rotina adicionais não descritas neste documento a fim de concluir a síntese das moléculas desejadas. Um versado na técnica também reconhecerá que pode ser possível obter a síntese das moléculas desejadas ao realizar algumas das etapas das vias sintéticas em uma ordem diferente da que foi descrita. Um versado na técnica também reconhecerá que pode ser possível realizar interconversões de grupos funcionais padronizados ou reações de substituição em moléculas desejadas para introduzir ou modificar substituintes.[000426] It is recognized that some reagents and reaction conditions may not be compatible with certain functionalities that may be present in certain molecules of Formula One and certain molecules used in the preparation of certain molecules of Formula One. In such cases, it may be necessary use standard protection and deprotection protocols widely reported in the literature and well known to a person skilled in the art. Furthermore, in some cases, it may be necessary to perform additional routine synthetic steps not described in this document in order to complete the synthesis of the desired molecules. One skilled in the art will also recognize that it may be possible to obtain the synthesis of the desired molecules by carrying out some of the steps in the synthetic pathways in a different order than that described. One skilled in the art will also recognize that it may be possible to carry out standardized functional group interconversions or substitution reactions on desired molecules to introduce or modify substituents.

Ensaios BiológicosBiological Tests

[000427] Os bioensaios seguintes contra lagarta da beterraba (Spodoptera exigua), lagarta mede-palmo (Trichoplusia ni), pulgão do pessegueiro (Myzus persicae), e mosquito da febre amarela (Aedes aegypti) estão incluídos neste documento devido ao dano que infligem. Além disso, a lagarta da beterraba e a lagarta mede-palmo são duas boas espécies indicadoras para uma ampla variedade de pragas mas- tigadoras. Além do mais, o pulgão do pessegueiro é uma boa espécie indicadora para uma ampla variedade de pragas que se alimentam de seiva. Os resultados com esses três indicadores juntamente com o mosquito da febre amarela mostram a ampla utilidade das moléculas da Fórmula Um no controle de pragas dos Filos Arthropoda, Mollusca e Nematoda (Drewes et al.)Exemplo A: Bioensaios em lagarta da beterraba (Spodoptera exigua, LAPHEG) ("BAW") e lagarta mede-palmo (Trichoplusia ni, TRIPNI) ("CL")[000427] The following bioassays against beet caterpillar (Spodoptera exigua), mede-palm caterpillar (Trichoplusia ni), peach aphid (Myzus persicae), and yellow fever mosquito (Aedes aegypti) are included in this document due to the damage they inflict . In addition, the beet worm and the palm worm are two good indicator species for a wide variety of chewing pests. Furthermore, the peach aphid is a good indicator species for a wide variety of sap-eating pests. The results with these three indicators together with the yellow fever mosquito show the wide utility of the Formula One molecules in the control of pests of Phyla Arthropoda, Mollusca and Nematoda (Drewes et al.)Example A: Bioassays on beet caterpillar (Spodoptera exigua) , LAPHEG) ("BAW") and spaniel caterpillar (Trichoplusia ni, TRIPNI) ("CL")

[000428] A lagarta da beterraba é uma praga grave de preocupação econômica para alfafa, aspargos, beterrabas, cítricos, milho, algodão, cebolas, ervilhas, pimentas, batatas, soja, beterraba sacarina, girassol, tabaco e tomate, entre outras culturas. É nativa do Sul da Ásia, mas agora é encontrada também na África, Austrália, Japão, América do Norte e Europa Meridional. As larvas podem se alimentar em grandes enxames, causando perdas devastadoras nos cultivos. É conhecida por ser resistente a vários pesticidas.[000428] Beetworm is a serious pest of economic concern to alfalfa, asparagus, beetroot, citrus, corn, cotton, onions, peas, peppers, potatoes, soybeans, sugar beet, sunflower, tobacco and tomato, among other crops. It is native to South Asia, but is now also found in Africa, Australia, Japan, North America and Southern Europe. Larvae can feed in large swarms, causing devastating crop losses. It is known to be resistant to various pesticides.

[000429] A lagarta mede-palmo é uma praga grave encontrada em todo o mundo. Ela ataca a alfafa, feijão, beterraba, brócolis, couve de bruxelas, repolho, melão, couve-flor, aipo, couve galega, algodão, pepinos, berinjelas, couves, alface, melões, mostarda, salsa, ervilhas, pimentas, batatas, soja, espinafre, abóbora, tomate, nabos e melancias, entre outras culturas. Essa espécie é muito destrutiva às plantas devido ao seu apetite voraz. As larvas consomem três vezes o seu peso diariamente. Os locais de alimentação são marcados por grandes acumulações de matéria fecal úmida e pegajosa que pode contribuir para maiores pressões de doenças, causando assim problemas secundários nas plantas que se encontram no local de cultivo. É conhecida por ser resistente a vários pesticidas.[000429] The spanish caterpillar is a serious pest found all over the world. It attacks alfalfa, beans, beets, broccoli, Brussels sprouts, cabbage, melon, cauliflower, celery, kale, cotton, cucumbers, eggplants, kale, lettuce, melons, mustard, parsley, peas, peppers, potatoes, soybeans, spinach, pumpkin, tomatoes, turnips and watermelons, among other crops. This species is very destructive to plants due to its voracious appetite. Larvae consume three times their weight daily. Feeding sites are marked by large accumulations of wet, sticky faecal matter that can contribute to increased disease pressures, thus causing secondary problems for plants in the growing site. It is known to be resistant to various pesticides.

[000430] Por conseguinte, em vista dos fatores acima, o controle dessas pragas é importante. Além disso, moléculas que controlam essas pragas (BAW e CL) e que são conhecidas como pragas mastiga- doras serão úteis no controle de outras pragas que mastigam vegetais.[000430] Therefore, in view of the above factors, the control of these pests is important. In addition, molecules that control these pests (BAW and CL) and which are known as chewing pests will be useful in controlling other pests that chew vegetables.

[000431] Certas moléculas divulgadas no presente documento foram testadas contra BAW e CL usando procedimentos descritos nos exemplos a seguir. Ao relatar os resultados, a "Tabela de Classificação de BAW & CL" foi usada (Vide Seção de Tabela).[000431] Certain molecules disclosed herein were tested against BAW and CL using procedures described in the examples below. When reporting the results, the "BAW & CL Ranking Table" was used (See Table Section).

Bioensaios em BAWBAW Bioassays

[000432] Os bioensaios em BAW foram conduzidos usando um ensaio em bandeja de dieta com 128 poços. Uma a cinco larvas de BAW em segundo instar foram colocadas em cada poço (3 mL) da bandeja de dieta que foi previamente preenchida com aproximadamente 1,5 mL de dieta artificial a qual 50 μg/cm2 da molécula de teste (dissolvida em 50 μL de 90:10 de mistura de acetona-água) foram aplicados (em cada um dos oito poços) e, então, foram secas. As bandejas foram cobertas com uma tampa autoadesiva clara, ventiladas para permitir a troca de gás, e mantidas a 25°C, em período de luz-escuro de 14:10 durante cinco a sete dias. O percentual de mortalidade foi registrado para as larvas em cada poço; retirou-se a média da atividade nos oito poços. Os resultados estão indicados na tabela intitulada "Tabela ABC: Resultados Biológicos" (Vide Seção de Tabela).[000432] The BAW bioassays were conducted using a 128-well diet tray assay. One to five second instar BAW larvae were placed in each well (3 mL) of the diet tray that was previously filled with approximately 1.5 mL of artificial diet which 50 μg/cm2 of the test molecule (dissolved in 50 μL) 90:10 acetone-water mixture) were applied (in each of the eight wells) and then dried. The trays were covered with a clear self-adhesive lid, ventilated to allow gas exchange, and kept at 25°C in a light-dark period of 14:10 for five to seven days. Percent mortality was recorded for larvae in each well; the average of the activity in the eight wells was taken. The results are indicated in the table entitled "Table ABC: Biological Results" (See Table Section).

Bioensaios em CLBioassays in CL

[000433] Os bioensaios em CL foram conduzidos usando um ensaio em bandeja de dieta de 128 poços. Uma a cinco larvas de CL em segundo instar foram colocadas em cada poço (3 mL) da bandeja de dieta que foi previamente preenchida com aproximadamente 1 mL de dieta artificial a qual 50 μg/cm2 da molécula de teste (dissolvida em 50 μL de 90:10 de mistura de acetona-água) foram aplicados (em cada um dos oito poços) e, então, foram secas. As bandejas foram cobertas com uma tampa autoadesiva clara, ventiladas para permitir a troca de gás, e mantidas a 25°C, em período de luz-escuro de 14:10 durante cinco a sete dias. O percentual de mortalidade foi registrado para as larvas em cada poço; retirou-se a média da atividade nos oito poços. Os resultados estão indicados na tabela intitulada "Tabela ABC: Resultados Biológicos" (Vide Seção de Tabela).Exemplo B: Bioensaios em pulgão do pessegueiro (Myzus persicae, MYZUPE) ("GPA").[000433] LC bioassays were conducted using a 128-well diet tray assay. One to five second instar CL larvae were placed in each well (3 mL) of the diet tray that was previously filled with approximately 1 mL of artificial diet which 50 μg/cm2 of the test molecule (dissolved in 50 μL of 90 :10 acetone-water mixture) were applied (in each of the eight wells) and then dried. The trays were covered with a clear self-adhesive lid, ventilated to allow gas exchange, and kept at 25°C in a light-dark period of 14:10 for five to seven days. Percent mortality was recorded for larvae in each well; the average of the activity in the eight wells was taken. The results are indicated in the table entitled "Table ABC: Biological Results" (See Table Section).Example B: Bioassays on peach aphid (Myzus persicae, MYZUPE) ("GPA").

[000434] O GPA é a praga de pulgões mais significativa dos pesse-gueiros, causando diminuição no crescimento, enrugamento das folhas e morte de vários tecidos. É perigoso também, pois atua como um vetor para o transporte de vírus de plantas, tais como vírus Y da batata e vírus do enrolamento da folha da batata em membros da família Sola- naceae das solenáceas/batata e vários vírus do mosaico em muitos outros cultivos alimentares. O GPA ataca plantas como brócolis, bar- dana, repolho, cenoura, couve-flor, nabo, berinjela, feijão verde, alface, macadâmia, papaia, pimentão, batata-doce, tomate, agrião e abobri- nha, entre outras culturas. O GPA também ataca muitos cultivos ornamentais como cravo, crisântemo, repolho branco florido, poinsétia e rosas. O GPA desenvolveu resistência contra muitos pesticidas. Atualmente, é a praga que possui o terceiro maior número de casos relatados de resistência de insetos (Sparks et al.). Por conseguinte, em vista dos fatores acima, o controle dessa praga é importante. Além do mais, moléculas que controlam essa praga (GPA), que é conhecida como uma praga que se alimenta de seiva, são úteis no controle de outras pragas que se alimentam da seiva de plantas.[000434] GPA is the most significant aphid pest of peach trees, causing decreased growth, wrinkling of leaves and death of various tissues. It is also dangerous as it acts as a vector for the transport of plant viruses such as potato Y virus and potato leaf roll virus in members of the Solanaceae/potato family Solanaceae and various mosaic viruses in many others food crops. GPA attacks plants such as broccoli, burdock, cabbage, carrots, cauliflower, turnips, eggplant, green beans, lettuce, macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress and zucchini, among other crops. GPA also attacks many ornamental crops such as cloves, chrysanthemum, white flowered cabbage, poinsettia and roses. GPA has developed resistance against many pesticides. Currently, it is the pest that has the third largest number of reported cases of insect resistance (Sparks et al.). Therefore, in view of the above factors, controlling this pest is important. Furthermore, molecules that control this pest (GPA), which is known as a sap-feeding pest, are useful in controlling other pests that feed on plant sap.

[000435] Certas moléculas divulgadas no presente documento foram testadas contra GPA usando procedimentos descritos nos exemplos a seguir. Ao relatar os resultados, a "Tabela de Classificação de GPA & YFM" foi usada (Vide Seção de Tabela).[000435] Certain molecules disclosed herein were tested against GPA using procedures described in the examples below. When reporting the results, the "GPA & YFM Ranking Table" was used (See Table Section).

[000436] Mudas de repolho cultivadas em potes de 3 polegadas com 2-3 folhas verdadeiras pequenas (3-5 cm) foram usadas como substrato de teste. As mudas foram infestadas com 20-50 GPA (adulto áptero e estágios de ninfa) um dia antes da aplicação química. Quatro potes com mudas individuais foram usados para cada tratamento. As moléculas de teste (2 mg) foram dissolvidas em 2 mL de solvente de aceto- na/metanol (1:1), formando soluções de estoque de 1000 ppm de molécula de teste. As soluções de estoque foram diluídas 5X com 0,025% de Tween 20 em água para obter a solução em 200 ppm de molécula de teste. Um pulverizador do tipo aspirador portátil foi usado para pulverizar uma solução em ambos os lados das folhas de repolho até o escoamento. Plantas de referência (controle de solvente) foram pulverizadas com diluente contendo apenas 20% em volume de solvente de aceto- na/metanol (1:1). As plantas tratadas foram mantidas em uma sala de espera durante três dias a aproximadamente 25°C e umidade relativa ambiente (RH) antes da classificação. A avaliação foi realizada contando o número de afídios vivos por planta em um microscópio. O percentual de controle foi medido usando a fórmula de correção de Abbott (W. S. Abbott, "A Method of Computing the Effectiveness of an Insecticide" J. Econ. Entomol. 18 (1925), pp,265-267) conforme se segue. % de Controle Corrigido = 100 * (X - Y) / X onde X = N° de afídios vivos nas plantas de controle de solvente e Y = N° de afídios vivos nas plantas tratadas. Os resultados estão indicados na tabela intitulada "Tabela ABC: Resultados Biológicos" (Vide Seção de Tabela).Exemplo C: Bioensaios em mosquito da febre amarela (Aedes aegypti, AEDSAE) ("YFM").[000436] Cabbage seedlings grown in 3-inch pots with 2-3 small (3-5 cm) true leaves were used as a test substrate. Seedlings were infested with 20-50 GPA (apterous adult and nymph stages) one day before chemical application. Four pots with individual seedlings were used for each treatment. Test molecules (2 mg) were dissolved in 2 mL of acetone/methanol (1:1) solvent, forming 1000 ppm test molecule stock solutions. Stock solutions were diluted 5X with 0.025% Tween 20 in water to obtain the solution at 200 ppm of test molecule. A portable vacuum-type sprayer was used to spray a solution on both sides of the cabbage leaves until runoff. Reference plants (solvent control) were sprayed with thinner containing only 20% by volume of acetone/methanol (1:1) solvent. Treated plants were kept in a holding room for three days at approximately 25°C and ambient relative humidity (RH) prior to classification. The evaluation was carried out by counting the number of live aphids per plant under a microscope. Percent control was measured using the Abbott correction formula (W.S. Abbott, "A Method of Computing the Effectiveness of an Insecticide" J. Econ. Entomol. 18 (1925), pp.265-267) as follows. % Corrected Control = 100 * (X - Y) / X where X = N° of live aphids on solvent control plants and Y = N° of live aphids on treated plants. The results are indicated in the table entitled "Table ABC: Biological Results" (See Table Section).Example C: Yellow fever mosquito (Aedes aegypti, AEDSAE) ("YFM") mosquito bioassays.

[000437] O YFM prefere se alimentar de humanos durante o dia, sendo encontrado com mais frequência em ou próximo a habitações de seres humanos. O YFM é um vetor que transmite várias doenças. É um mosquito que pode espalhar os vírus da dengue e febre amarela. A febre amarela é a segunda doença transmitida por mosquito mais pe-rigosa, depois da malária. É uma doença hemorrágica viral aguda e até 50% das pessoas gravemente afetadas sem tratamento morrerão de febre amarela. Existem 200,000 casos estimados de febre amarela, causando 30,000 mortes por ano em todo o mundo. A dengue é uma doença viral desagradável que às vezes é chamada de "febre quebra ossos" ou "febre do coração dolorido" devido à dor intensa que ela produz. A dengue mata por ano cerca de 20,000 pessoas. Por conse-guinte, em vista dos fatores acima, o controle dessa praga é importante. Além disso, moléculas que controlam essa praga (YFM), que é conhecida como a praga sugadora, são úteis no controle de outras pragas que causam sofrimento humano e animal.[000437] YFM prefers to feed on humans during the day, being found more often in or near human dwellings. YFM is a vector that transmits several diseases. It is a mosquito that can spread dengue and yellow fever viruses. Yellow fever is the second most dangerous mosquito-borne disease after malaria. It is an acute viral hemorrhagic disease and up to 50% of severely affected people without treatment will die of yellow fever. There are an estimated 200,000 cases of yellow fever, causing 30,000 deaths a year worldwide. Dengue is an unpleasant viral illness that is sometimes called "bone break fever" or "heart aching fever" because of the intense pain it produces. Dengue fever kills about 20,000 people a year. Therefore, in view of the above factors, control of this pest is important. In addition, molecules that control this pest (YFM), which is known as the sucking pest, are useful in controlling other pests that cause human and animal suffering.

[000438] Certas moléculas divulgadas no presente documento foram testadas contra YFM usando procedimentos descritos no parágrafo a seguir. Ao relatar os resultados, a "Tabela de Classificação de GPA & YFM" foi usada (Vide Seção de Tabela).[000438] Certain molecules disclosed herein were tested against YFM using procedures described in the paragraph below. When reporting the results, the "GPA & YFM Ranking Table" was used (See Table Section).

[000439] São usadas placas mestre contendo 400 μg de uma molécula dissolvida em 100 μL de sulfóxido de dimetila (DMSO) (equivalente a uma solução de 4000 ppm). Uma placa mestre de moléculas montadas contém 15 μL por poço. E essa placa, 135 μL de uma mistura de água/acetona a 90:10 é adicionada em cada poço. Um robô é programado para dispenser aspirações de 15 μL a partir da placa mestre dentro de uma placa rasa de 96 poços vazia (placa "irmã"). Há 6 reps (placas "irmãs") criadas por mestre. As placas "irmãs" criadas são imediatamente infestadas com larvas de YFM.[000439] Master plates containing 400 μg of a molecule dissolved in 100 μL of dimethyl sulfoxide (DMSO) (equivalent to a 4000 ppm solution) are used. A master plate of assembled molecules contains 15 µL per well. And that plate, 135 μL of a 90:10 water/acetone mixture is added to each well. A robot is programmed to dispense 15 µL aspirations from the master plate into an empty 96-well shallow plate ("sister" plate). There are 6 reps ("sister" cards) created per DM. The "sister" plaques created are immediately infested with YFM larvae.

[000440] No dia antes das placas serem tratadas, ovos de mosquito são colocados em água Millipore contendo fígado em pó para iniciar a eclosão de ovos (4 g. em 400 mL). Depois que as placas "irmãs" são criadas usando o robô, elas são infestadas com 220 μL de fígado em pó/mistura de larvas de mosquito (larvas com cerca de 1 dia de idade). Depois que as placas são infestadas com ovos de mosquito, uma tampa não evaporativa é usada para cobrir a placa a fim de reduzir a secagem. As placas são mantidas a temperatura ambiente durante 3 dias para graduação. Após 3 dias, cada poço é observado e fornecido um escore com base na mortalidade. Os resultados estão indicados na tabela intitulada "Tabela ABC: Resultados Biológicos" (Vide Seção de Tabela).Sais de adição de ácido, derivados de sais, solvatos, derivados de éster, polimorfos, isótopos e radionuclídeos agricolamente aceitáveis.[000440] The day before the plates are treated, mosquito eggs are placed in Millipore water containing powdered liver to initiate egg hatching (4 g. in 400 mL). After the "sister" plates are created using the robot, they are infested with 220 µL of liver powder/mosquito larvae mixture (about 1 day old larvae). After the plates are infested with mosquito eggs, a non-evaporative lid is used to cover the plate to reduce drying. Plates are kept at room temperature for 3 days for graduation. After 3 days, each well is observed and given a score based on mortality. The results are indicated in the table entitled "Table ABC: Biological Results" (See Table Section). Acid addition salts, salt derivatives, solvates, ester derivatives, polymorphs, isotopes and agriculturally acceptable radionuclides.

[000441] As moléculas da Fórmula Um podem ser formuladas em sais de adição de ácido agricolamente aceitáveis. A título de um exemplo não limitante, uma função de amina pode formar sais com ácidos clorídrico, bromídrico, sulfúrico, fosfórico, acético, benzoico, cítrico, malônico, salicílico, málico, fumárico, oxálico, succínico, tartárico, láctico, glucônico, ascórbico, maleico, aspártico, benzenossulfônico, metanossulfônico, etanossulfônico, hidroxil-metanossulfônico e hidró- xietanossulfônico. Além disso, a título de um exemplo não limitante, uma função de ácido pode formar sais, incluindo aqueles derivados de metais alcalinos ou alcalinos-terrosos e aqueles derivados de amônia e aminas. Exemplos de cátions preferenciais incluem sódio, potássio e magnésio.[000441] Molecules of Formula One can be formulated into agriculturally acceptable acid addition salts. By way of non-limiting example, an amine function can form salts with hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic acid , maleic, aspartic, benzenesulfonic, methanesulfonic, ethanesulfonic, hydroxyl-methanesulfonic and hydroxyethanesulfonic. Furthermore, by way of non-limiting example, an acid function can form salts, including those derived from alkali or alkaline earth metals and those derived from ammonia and amines. Examples of preferred cations include sodium, potassium and magnesium.

[000442] Moléculas da Fórmula Um podem ser formuladas em derivados de sais. A título de um exemplo não limitante, um derivado de sal pode ser preparado ao colocar uma base livre em contato com uma quantidade suficiente do ácido desejado para produzir um sal. Uma base livre pode ser regenerada ao tratar o sal com uma solução de base aquosa diluída adequada, tal como hidróxido de sódio aquoso diluído, carbonato de potássio, amônia e bicarbonato de sódio. Como um exemplo, em muitos casos, um pesticida, tal como 2,4-D é feito mais solúvel em água ao convertê-lo em seu sal dimetilamina.[000442] Molecules of Formula One can be formulated into salt derivatives. As a non-limiting example, a salt derivative can be prepared by contacting a free base with a sufficient amount of the desired acid to produce a salt. A free base can be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. As an example, in many cases a pesticide such as 2,4-D is made more soluble in water by converting it to its dimethylamine salt.

[000443] Moléculas da Fórmula Um podem ser formuladas em complexos estáveis com um solvente de forma que o complexo permanece intacto após a remoção do solvente não complexado. Esses complexos são geralmente chamados de "solvatos". No entanto, é particularmente desejável formar hidratos estáveis com água como o solvente.[000443] Molecules of Formula One can be formulated into stable complexes with a solvent such that the complex remains intact after removal of the uncomplexed solvent. These complexes are often called "solvates". However, it is particularly desirable to form stable hydrates with water as the solvent.

[000444] Moléculas da Fórmula Um contendo uma funcionalidade ácida podem ser feitas em derivados de éster. Esses derivados de éster podem então ser aplicados da mesma maneira como são aplicadas as moléculas divulgadas no presente documento.[000444] Molecules of Formula One containing an acidic functionality can be made into ester derivatives. These ester derivatives can then be applied in the same way as the molecules disclosed herein are applied.

[000445] Moléculas da Fórmula Um pode ser feitas como vários po-limorfos cristalinos. O polimorfismo é importante no desenvolvimento de agroquímicos, visto que diferentes polimorfos cristalinos ou estruturas da mesma molécula podem possuir propriedades físicas bem como desempenhos biológicos amplamente diferentes.[000445] Formula One molecules can be made as various crystalline polymorphs. Polymorphism is important in the development of agrochemicals, as different crystalline polymorphs or structures of the same molecule can have vastly different physical properties as well as biological performances.

[000446] Moléculas da Fórmula Um podem ser feitas com isótopos diferentes. São de importância particular as moléculas com 2H (conhe-cidas também como deutério) ou 3H (conhecidas também como trítio) no lugar de 1H. Moléculas da Fórmula Um podem ser feitas com radio- nuclídeos diferentes. São de importância particular as moléculas com 14C (conhecidas também como radiocarbono). Moléculas da Fórmula Um contendo deutério, trítio ou 14C podem ser usadas em estudos biológicos que permitem o rastreamento em processos químicos e fisiológicos e estudos de meia-vida, bem como estudos MoA.[000446] Formula One molecules can be made with different isotopes. Of particular importance are molecules with 2H (also known as deuterium) or 3H (also known as tritium) in place of 1H. Formula One molecules can be made with different radionuclides. Of particular importance are 14C molecules (also known as radiocarbon). Formula One molecules containing deuterium, tritium or 14C can be used in biological studies that allow tracking of chemical and physiological processes and half-life studies as well as MoA studies.

Combinaçõescombinations

[000447] Em outra modalidade da presente invenção, moléculas da Fórmula Um podem ser usadas em combinação (tal como em uma mistura composicional ou uma aplicação simultânea ou sequencial) com um ou mais princípios ativos.[000447] In another embodiment of the present invention, molecules of Formula One can be used in combination (such as in a compositional mixture or a simultaneous or sequential application) with one or more active principles.

[000448] Em outra modalidade da presente invenção, moléculas da Fórmula Um podem ser usadas em combinação (tal como em uma mistura composicional ou uma aplicação simultânea ou sequencial) com um ou mais princípios ativos contendo um MoA que é idêntico à, similar à, mas muito provavelmente - diferente de, MoA das moléculas da Fórmula Um.[000448] In another embodiment of the present invention, Formula One molecules can be used in combination (such as in a compositional mixture or a simultaneous or sequential application) with one or more active principles containing an MoA that is identical to, similar to, but most likely - other than the MoA of Formula One molecules.

[000449] Em outra modalidade, moléculas da Fórmula Um podem ser usadas em combinação (tal como, em uma mistura composicional ou aplicação simultânea ou sequencial) com uma ou mais moléculas con-tendo propriedades acaricida, algicida, avicida, bactericida, fungicida, herbicida, inseticida, moluscicida, nematicida, rodenticida e/ou virucida.[000449] In another embodiment, molecules of Formula One can be used in combination (such as, in a compositional mixture or simultaneous or sequential application) with one or more molecules having acaricidal, algaecide, avicide, bactericidal, fungicidal, herbicide properties , insecticide, molluscicide, nematicide, rodenticide and/or virucidal.

[000450] Em outra modalidade, as moléculas da Fórmula Um pode ser usadas em combinação (tal como em uma mistura composicional ou uma aplicação simultânea ou sequencial) com uma ou mais moléculas que são produtos com efeito antialimentar, repelentes de pássaros, quimioesterilizante, fitoprotetores contra herbicidas, atrativos de insetos, repelentes de insetos, repelentes de mamíferos, disruptores de acasalamento, ativadores de plantas, reguladores de crescimento de plantas e/ou sinergistas.[000450] In another embodiment, the Formula One molecules can be used in combination (such as in a compositional mixture or a simultaneous or sequential application) with one or more molecules that are anti-food, bird repellent, chemosterilant, phytoprotective products against herbicides, insect attractants, insect repellents, mammal repellents, mating disruptors, plant activators, plant growth regulators and/or synergists.

[000451] Em outra modalidade da presente invenção, moléculas da Fórmula Um também podem ser usadas em combinação (tal como em uma mistura composicional ou uma aplicação simultânea ou sequencial) com um ou mais biopesticidas.[000451] In another embodiment of the present invention, Formula One molecules can also be used in combination (such as in a compositional mixture or a simultaneous or sequential application) with one or more biopesticides.

[000452] Em outra modalidade, em uma composição pesticida, com-binações de uma molécula da Fórmula Um e um princípio ativo podem ser usadas em uma ampla variedade de razões de peso. Por exemplo, em uma mistura de dois componentes, a razão de peso de uma molécula da Fórmula Um para um princípio ativo, as razões de peso na Tabela B podem ser usadas. No entanto, em geral, razões de peso menores do que cerca de 10:1 a cerca de 1:10 são preferenciais. Às vezes, é preferencial também usar uma mistura de três, quatro, cinco, seis, sete ou mais componentes compreendendo uma molécula da Fórmula Um e um ou mais princípios ativos adicionais.[000452] In another embodiment, in a pesticide composition, combinations of a Formula One molecule and an active ingredient can be used in a wide variety of weight ratios. For example, in a two-component mixture, the weight ratio of a Formula One molecule to an active ingredient, the weight ratios in Table B can be used. However, in general, weight ratios less than about 10:1 to about 1:10 are preferred. Sometimes, it is also preferred to use a mixture of three, four, five, six, seven or more components comprising a molecule of Formula One and one or more additional active ingredients.

[000453] As razões de peso de uma molécula da Fórmula Um para um princípio ativo podem ser representadas também como X:Y; onde X são as partes em peso de uma molécula da Fórmula Um e Y são as partes em peso do princípio ativo. O intervalo numérico das partes em peso para X é 0 < X < 100 e as partes em peso para Y é 0 < Y < 100 e é mostrado graficamente na TABELA C. A título de exemplo não limi- tante, a razão de peso de uma molécula da Fórmula Um para um princípio ativo pode ser 20:1.[000453] The weight ratios of a molecule of Formula One to an active principle can also be represented as X:Y; where X are the parts by weight of a molecule of Formula One and Y are the parts by weight of the active ingredient. The numerical range of parts by weight for X is 0 < X < 100 and parts by weight for Y is 0 < Y < 100 and is shown graphically in TABLE C. By way of non-limiting example, the weight ratio of a Formula One molecule for an active ingredient can be 20:1.

[000454] Intervalos de razões de peso de uma molécula da Fórmula um para um princípio ativo podem ser representados como X1:Y1 para X2:Y2, onde X e Y são definidos abaixo.[000454] Ranges of weight ratios of a molecule of Formula One to an active ingredient can be represented as X1:Y1 to X2:Y2, where X and Y are defined below.

[000455] Em uma modalidade, o intervalo de razões de peso pode ser X1:Y1 para X2:Y2, onde X1 > Y1 e X2 < Y2. A título de exemplo não limitante, o intervalo de uma razão de peso de uma molécula da Fórmula Um para um princípio ativo pode estar entre 3:1 e 1:3, inclusive dos desfechos.[000455] In one modality, the range of weight ratios can be X1:Y1 to X2:Y2, where X1 > Y1 and X2 < Y2. As a non-limiting example, the range of a weight ratio of a Formula One molecule to an active ingredient can be between 3:1 and 1:3, inclusive of the endpoints.

[000456] Em uma modalidade, o intervalo das razões de peso pode ser X1:Y1 para X2:Y2, onde X1 > Y1 e X2 > Y2. A título de exemplo não limitante, o intervalo de uma razão de peso de uma molécula da Fórmula Um para um princípio ativo pode estar entre 15:1 e 3:1, inclusive dos desfechos.[000456] In one mode, the range of weight ratios can be X1:Y1 to X2:Y2, where X1 > Y1 and X2 > Y2. As a non-limiting example, the range of a weight ratio of a Formula One molecule to an active ingredient can be between 15:1 and 3:1, inclusive of the endpoints.

[000457] Em outra modalidade, o intervalo das razões de peso pode ser X1:Y1 para X2:Y2, onde X1 < Y1 e X2 < Y2. A título de exemplo não limitante, o intervalo das razões de peso de uma molécula da Fórmula Um para um princípio ativo pode estar entre cerca de 1:3 e cerca de 1:20, inclusive dos desfechos.[000457] In another mode, the range of weight ratios can be X1:Y1 to X2:Y2, where X1 < Y1 and X2 < Y2. By way of non-limiting example, the range of weight ratios of a Formula One molecule to an active ingredient can be between about 1:3 and about 1:20, inclusive of endpoints.

FormulaçõesFormulations

[000458] Um pesticida muitas vezes não é adequado para aplicação na sua forma pura. Geralmente, é necessário adicionar outras subs tâncias para que o pesticida possa ser utilizado na concentração ne-cessária e na forma apropriada, permitindo a fácil aplicação, manuseio, transporte, armazenamento e atividade máxima do pesticida. Assim, pesticidas são formulados em, por exemplo, iscas, emulsões con-centradas, pós, concentrados emulsificáveis, fumigantes, géis, grânulos, microencapsulamentos, tratamentos com sementes, concentrados em suspensão, suspoemulsões, comprimidos, líquidos solúveis em água, grânulos dispersíveis em água ou material dispersível seco, pós molháveis e soluções de ultra baixo volume.[000458] A pesticide is often not suitable for application in its pure form. It is usually necessary to add other substances so that the pesticide can be used in the required concentration and in the proper form, allowing for easy application, handling, transport, storage and maximum pesticide activity. Thus, pesticides are formulated in, for example, baits, concentrated emulsions, powders, emulsifiable concentrates, fumigants, gels, granules, microencapsulations, seed treatments, suspension concentrates, suspoemulsions, tablets, water-soluble liquids, granules dispersible in water or dry dispersible material, wettable powders and ultra low volume solutions.

[000459] Os pesticidas são aplicados com mais frequência como suspensões aquosas ou emulsões preparadas a partir de formulações concentradas de tais pesticidas. Essas formulações solúveis em água, dispersíveis em água ou emulsificáveis em água podem ser tanto sólidas, geralmente conhecidas como pós molháveis, grânulos dispersível em água, líquidos geralmente conhecidos como um concentrados emulsificáveis ou suspensões aquosas. Pós solúveis que podem ser compactados para formar grânulos dispersíveis em água compreendem uma mistura integral do pesticida, um veículo e tensoativos. A concentração do pesticida é geralmente de cerca de 10% a cerca de 90% em peso. O veículo é geralmente selecionado dentre argilas ata- pulgitas, as argilas montmorillonitas, as terras de diatomáceas ou os silicatos purificados. Tensoativos eficazes compreendendo cerca de 0,5 % a cerca de 10% do pó molhável são encontrados dentre ligninas sulfonadas, naftalenossulfonatos condensados, naftalenossulfonatos, alquilbenzenossulfonatos, sulfatos de alquila e tensoativos não iônicos tais como adutos de óxido de etileno de fenóis de alquila.[000459] Pesticides are most often applied as aqueous suspensions or emulsions prepared from concentrated formulations of such pesticides. Such water-soluble, water-dispersible or water-emulsifiable formulations can be either solid, generally known as wettable powders, water-dispersible granules, liquids generally known as an emulsifiable concentrate, or aqueous suspensions. Soluble powders which can be compacted to form water dispersible granules comprise an integral mixture of the pesticide, a carrier and surfactants. The concentration of the pesticide is generally from about 10% to about 90% by weight. The vehicle is generally selected from attapulgite clays, montmorillonite clays, diatomaceous earths or purified silicates. Effective surfactants comprising about 0.5% to about 10% of the wettable powder are found among sulfonated lignins, condensed naphthalene sulfonates, naphthalene sulfonates, alkylbenzene sulfonates, alkyl sulfates, and nonionic surfactants such as ethylene oxide adducts of alkyl phenols.

[000460] Concentrados emulsificáveis de pesticidas compreendem uma concentração conveniente de um pesticida, tal como de cerca de 50 a cerca de 500 gramas por litro do líquido dissolvido em um veículo que é um solvente miscível em água ou uma mistura de solvente or- gânico imiscível em água e emulsificantes. Solventes orgânicos úteis incluem aromáticos, especialmente frações de xileno e petróleo, espe-cialmente as porções de petróleo naftalênicas e olefínicas de elevada ebulição, tal como nafta aromática pesada. Outros solventes orgânicos também podem ser usados, tais como os solventes terpênicos, incluindo derivados de rosina, cetonas alifáticas, tal como ciclo-hexanona, e álcoois complexos, tal como 2-etoxietanol. Emulsificantes adequados para concentrados emulsificáveis são selecionados dentre tensoativos aniônicos e não iônicos convencionais.[000460] Emulsifiable pesticide concentrates comprise a convenient concentration of a pesticide, such as from about 50 to about 500 grams per liter of liquid dissolved in a vehicle which is a water-miscible solvent or an immiscible organic solvent mixture in water and emulsifiers. Useful organic solvents include aromatics, especially xylene and petroleum fractions, especially the high-boiling naphthalene and olefinic petroleum moieties, such as heavy aromatic naphtha. Other organic solvents can also be used, such as terpenic solvents, including rosin derivatives, aliphatic ketones, such as cyclohexanone, and complex alcohols, such as 2-ethoxyethanol. Suitable emulsifiers for emulsifiable concentrates are selected from conventional anionic and nonionic surfactants.

[000461] Suspensões aquosas compreendem suspensões de pesticidas insolúveis em água dispersos em um veículo aquoso em uma concentração no intervalo de cerca de 5% a cerca de 50% em peso. As suspensões podem ser preparadas por moagem fina do pesticida e mistura vigorosa desta em um veículo composto por água e tensoati- vos. Ingredientes, tais como sais inorgânicos e gomas sintéticas ou naturais, também podem ser adicionados para aumentar a densidade e viscosidade do veículo aquoso. Muitas vezes é mais eficaz moer e misturar o pesticida ao mesmo tempo, preparando a mistura aquosa e homogeneizando-a em um instrumento, tal como um moinho de areia, moinho de bolas, ou homogeneizador tipo pistão. O pesticida em sus-pensão pode ser microencapsulado em polímero plástico.[000461] Aqueous suspensions comprise suspensions of water-insoluble pesticides dispersed in an aqueous vehicle at a concentration in the range of about 5% to about 50% by weight. Suspensions can be prepared by finely grinding the pesticide and vigorously mixing it into a vehicle composed of water and surfactants. Ingredients, such as inorganic salts and synthetic or natural gums, can also be added to increase the density and viscosity of the aqueous vehicle. It is often more effective to grind and mix the pesticide at the same time, preparing the aqueous mixture and homogenizing it in an instrument such as a sand mill, ball mill, or piston type homogenizer. The suspended pesticide can be microencapsulated in plastic polymer.

[000462] Dispersões em óleo (OD) compreendem suspensões de pesticidas insolúveis em solvente orgânico finamente dispersos em uma mistura de solvente orgânico e emulsificantes a uma concentração no intervalo de cerca de 2% a cerca de 50% em peso. Um ou mais pesticidas podem ser dissolvidos no solvente orgânico. Solventes or-gânicos úteis incluem aromáticos, especialmente frações de xileno e petróleo, especialmente as porções de petróleo naftalênicas e olefíni- cas de elevada ebulição, tal como nafta aromática pesada. Outros solventes podem incluir óleos vegetais, óleos de sementes e ésteres de vegetais e óleos de sementes. Emulsificantes adequados para disper-sões são selecionados a partir de tensoativos aniônicos e não aniôni- cos. Espessantes ou agentes gelificantes são adicionados na formulação de dispersões em óleo para modificar a reologia ou propriedades de fluxo do líquido e para evitar a separação e sedimentação das partículas ou gotas dispersas.[000462] Oil dispersions (OD) comprise suspensions of pesticides insoluble in organic solvent finely dispersed in a mixture of organic solvent and emulsifiers at a concentration in the range of about 2% to about 50% by weight. One or more pesticides can be dissolved in the organic solvent. Useful organic solvents include aromatics, especially xylene and petroleum fractions, especially the naphthalene petroleum moieties and high-boiling olefins, such as heavy aromatic naphtha. Other solvents can include vegetable oils, seed oils and vegetable esters and seed oils. Suitable emulsifiers for dispersions are selected from anionic and non-anionic surfactants. Thickeners or gelling agents are added in the formulation of oil dispersions to modify the rheology or flow properties of the liquid and to prevent separation and sedimentation of the dispersed particles or droplets.

[000463] Pesticidas podem ser aplicados também como composições granulares que são particularmente úteis para aplicações no solo. Composições granulares geralmente contém de cerca de 0,5% a cerca de 10% em peso do pesticida, disperso em um veículo que compreende argila ou uma substância similar. Essas formulações geralmente são preparadas ao dissolver o pesticida em um solvente adequado e aplicá-lo em um veículo granular que foi pré-formado para o tamanho de partícula adequado no intervalo de cerca de 0,5 a cerca de 3 mm. Essas composições também podem ser formuladas por criar uma massa ou pasta do veículo e da molécula, e então, triturar e secar para obter o tamanho de partícula granular desejada. Outra forma de grânulos é um grânulo emulsificável em água (EG). É uma formulação consistindo em grânulos a serem aplicados como uma emulsão de óleo em água convencional do(s) ingrediente(s) ativo, seja solubilizado ou diluído em um solvente orgânico após desintegração e dissolução em água. Grânulos emulsificáveis em água compreendem um ou vários princípios ativos, solubilizados ou diluídos em um solvente orgânico adequado que é (são) absorvidos em uma casca polimérica solúvel em água ou algum outro tipo de matriz solúvel ou insolúvel.[000463] Pesticides can also be applied as granular compositions which are particularly useful for soil applications. Granular compositions generally contain from about 0.5% to about 10% by weight of the pesticide, dispersed in a vehicle comprising clay or a similar substance. These formulations are generally prepared by dissolving the pesticide in a suitable solvent and applying it to a granular vehicle that has been preformed to the proper particle size in the range of about 0.5 to about 3 mm. These compositions can also be formulated by creating a mass or paste of the vehicle and molecule, and then grinding and drying to obtain the desired granular particle size. Another form of granules is a water-emulsifiable (EG) granule. It is a formulation consisting of granules to be applied as a conventional oil-in-water emulsion of the active ingredient(s), either solubilized or diluted in an organic solvent after disintegration and dissolution in water. Water-emulsifiable granules comprise one or more active principles, solubilized or diluted in a suitable organic solvent which is (are) adsorbed onto a water-soluble polymeric shell or some other type of soluble or insoluble matrix.

[000464] Pós que contém pesticida são preparados por misturar inti-mamente o pesticida em forma de pó com um veículo agrícola em pó adequado, como por exemplo, argila caulim, rocha vulcânica e seme-lhantes. Pós podem conter adequadamente de cerca de 1% a cerca de 10% do pesticida. Pós podem ser aplicados como um revestimento de sementes ou como uma aplicação de folhagem com uma máquina in- sufladora de pó.[000464] Pesticide-containing powders are prepared by intimately mixing the pesticide in powder form with a suitable powdered agricultural vehicle, such as, for example, kaolin clay, volcanic rock and the like. Powders can suitably contain from about 1% to about 10% of the pesticide. Powders can be applied as a seed coating or as a foliage application with a powder blowing machine.

[000465] É igualmente prático aplicar um pesticida na forma de uma solução em um solvente orgânico adequado, geralmente óleo de petróleo, tal como os óleos em spray que são amplamente usados na química agrícola.[000465] It is equally practical to apply a pesticide in the form of a solution in a suitable organic solvent, usually petroleum oil, such as spray oils that are widely used in agricultural chemistry.

[000466] Pesticidas também podem ser aplicados na forma de uma composição em aerossol. Nessas composições, o pesticida é dissolvido ou disperso em um veículo que é uma mistura propulsora geradora de pressão. A composição em aerossol é embalada em um recipiente do qual a mistura é dispensada através de uma válvula de atomização.[000466] Pesticides can also be applied in the form of an aerosol composition. In these compositions, the pesticide is dissolved or dispersed in a vehicle which is a pressure-generating propellant mixture. The aerosol composition is packaged in a container from which the mixture is dispensed through an atomizing valve.

[000467] Iscas de pesticidas são formadas quando o pesticida é mis-turado com alimento ou com um atrativo ou ambos. Quando as pragas comem a isca, elas também consomem o pesticida. Pesticidas podem ter a forma de grânulos, géis, pós dispersíveis, líquidos ou sólidos. Iscas podem ser usadas em ninhos de pragas.[000467] Pesticides baits are formed when the pesticide is mixed with food or an attractant or both. When pests eat the bait, they also consume the pesticide. Pesticides can take the form of granules, gels, dispersible powders, liquids or solids. Bait can be used in pest nests.

[000468] Fumigantes são pesticidas que possuem uma pressão de vapor relativamente alta e, portanto, podem existir como um gás em concentrações suficientes para matar pragas no solo ou espaços fe-chados. A toxicidade do fumigante é proporcional a sua concentração e o tempo de exposição. Eles são caracterizados por uma boa capacidade para difusão e atuam ao penetrar no sistema respiratório da praga e sendo absorvido através da cutícula da praga. Fumigantes são aplicados para controlar pragas de produtos estocados sob lâminas à prova de gás em salas ou construções vedadas a gás ou em câmaras especiais.[000468] Fumigants are pesticides that have a relatively high vapor pressure and therefore can exist as a gas in sufficient concentrations to kill pests in soil or enclosed spaces. The toxicity of the fumigant is proportional to its concentration and exposure time. They are characterized by a good diffusion capacity and act by penetrating the pest's respiratory system and being absorbed through the pest's cuticle. Fumigants are applied to control pests of products stored under gas-tight foils in gas-tight rooms or buildings or in special chambers.

[000469] Pesticidas podem ser microencapsulados ao suspender as partículas ou gotas de pesticida em polímeros plásticos ou vários tipos. Ao alterar a estrutura química do polímero ou ao alterar os fatores no processamento podem ser formadas microcápsulas de vários tama- nhos, solubilidade, espessura de parede e graus de penetrabilidade. Esses fatores regem a velocidade em que o princípio ativo dentro é liberado que, por sua vez, afeta o desempenho residual, velocidade de ação e odor do produto. As microcápsulas podem ser formuladas como concentrados de suspensão ou grânulos dispersíveis em água.[000469] Pesticides can be microencapsulated by suspending the particles or drops of pesticide in plastic polymers or various types. By changing the chemical structure of the polymer or by changing factors in processing, microcapsules of various sizes, solubility, wall thickness and degrees of penetrability can be formed. These factors govern the speed at which the active ingredient within is released which, in turn, affects the residual performance, speed of action and odor of the product. Microcapsules can be formulated as suspension concentrates or water dispersible granules.

[000470] Os concentrados de solução em óleo são feitos ao dissolver o pesticida em um solvente que reterá o pesticida na solução. Soluções em óleo de um pesticida geralmente fornecem knockdown mais rápido e matam as pragas do que outras formulações devido aos próprios solventes possuírem ação pesticida e a dissolução da graxa que cobre o tegumento aumentar a velocidade de absorção do pesticida. Outras vantagens de soluções em óleo incluem melhor estabilidade de armazenamento, melhor penetração de fendas e melhor adesão a su-perfícies oleosas.[000470] Solution-in-oil concentrates are made by dissolving the pesticide in a solvent that will retain the pesticide in solution. Oil solutions of a pesticide generally provide faster knockdown and kill pests than other formulations because the solvents themselves have pesticidal action and the dissolution of the grease covering the integument increases the pesticide's absorption speed. Other advantages of oil solutions include better storage stability, better crack penetration and better adhesion to oily surfaces.

[000471] Outra modalidade é uma emulsão óleo em água onde a emulsão compreende glóbulos oleosos em que cada um deles é fornecido com um revestimento cristalino líquido lamelar e são dispersos em uma fase aquosa, em que cada glóbulo oleoso compreende pelo menos uma molécula que é agricolamente ativa, sendo individualmente revestido por uma camada monolamelar ou oligolamelar, compreendendo: (1) pelo menos um agente ativo em superfície lipofílico não iônico, (2) pelo menos um agente ativo em superfície hidrofílico não iônico, e (3) pelo menos um agente ativo em superfície iônico, em que os glóbulos contém um diâmetro de partícula médio menor que 800 nanômetros.[000471] Another modality is an oil-in-water emulsion where the emulsion comprises oil globules each of which is provided with a lamellar liquid crystalline coating and are dispersed in an aqueous phase, wherein each oil globule comprises at least one molecule that is agriculturally active, being individually coated by a monolamellar or oligolamellar layer, comprising: (1) at least one nonionic lipophilic surface active agent, (2) at least one nonionic hydrophilic surface active agent, and (3) at least one ionic surface active agent, in which the globules contain an average particle diameter less than 800 nanometers.

Outros componentes da formulaçãoOther components of the formulation

[000472] Geralmente, quando as moléculas divulgadas na Fórmula Um são usadas em uma formulação, essa formulação pode conter também outros componentes. Esses componentes incluem, mas não estão limitados a, (esta é uma lista não abrangente e não mutualmente exclusiva) molhantes, expansores, adesivos, penetrantes, tampões, agentes sequestrantes, agentes de redução de deslocamento, agentes de compatibilidade, agentes antiespumantes, agentes de limpeza e emulsificantes. Alguns componentes são descritos a seguir.[000472] Generally, when the molecules disclosed in Formula One are used in a formulation, that formulation may also contain other components. These components include, but are not limited to, (this is a non-comprehensive and not mutually exclusive list) wetting agents, expanders, adhesives, penetrants, buffers, sequestering agents, displacement reducing agents, compatibility agents, defoaming agents, defoaming agents. cleaners and emulsifiers. Some components are described below.

[000473] Um agente molhante é uma substância que, quando adicionada a um líquido, aumenta o poder de espalhamento ou penetração do líquido ao reduzir a tensão interfacial entre o líquido e a superfície na qual está se espalhando. Agentes molhantes são usados para duas funções principais nas formulações agroquímicas: durante o processamento e fabricação para aumentar a taxa de molhagem dos pós em água a fim de criar concentrados para líquidos solúveis ou concentrados de suspensão; e durante a mistura de um produto com água em um tanque de pulverização para reduzir o tempo de molhagem de pós molháveis e para melhorar a penetração de água em grânulos disper- síveis em água. Exemplos de agentes molhantes usados no pó molhá- vel, concentrado de suspensão e formulações de grânulo dispersível em água são: lauril sulfato de sódio, dioctil sulfosuccinato de sódio; etoxilatos de fenol alquila; e etoxilatos de álcool alifático.[000473] A wetting agent is a substance that, when added to a liquid, increases the spreading or penetration power of the liquid by reducing the interfacial tension between the liquid and the surface on which it is spreading. Wetting agents are used for two main functions in agrochemical formulations: during processing and manufacturing to increase the wetting rate of powders in water to create soluble liquid concentrates or suspension concentrates; and during mixing of a product with water in a spray tank to reduce the wetting time of wettable powders and to improve water penetration into water-dispersible granules. Examples of wetting agents used in wettable powder, suspension concentrate and water dispersible granule formulations are: sodium lauryl sulfate, sodium dioctyl sulfosuccinate; alkyl phenol ethoxylates; and aliphatic alcohol ethoxylates.

[000474] Um agente dispersante é uma substância que absorve sobre a superfície das partículas, ajuda a preservar o estado de dispersão das partículas e previne que elas se reagrupem. Agentes disper- santes são adicionados às formulações agroquímicas para facilitar a dispersão e suspensão durante a fabricação e para garantir que as partículas se dispersem novamente em água em um tanque de pulverização. Eles são amplamente usados em pós molháveis, concentrados de suspensão e grânulos dispersíveis em água. Tensoativos que são usados como agentes dispersantes têm a capacidade de absorver bastante sobre uma superfície de partícula e fornecer uma barreira carregada ou estérica para o reagrupamento de partículas. Os tensoa- tivos mais comumente usados são os aniônicos, não iônicos ou mistu- ras dos dois tipos. Para formulações de pó molhável, os agentes dis- persantes mais comuns são lignossulfonatos de sódio. Para concen-trados de suspensão, a absorção e estabilização muito boas geralmente são obtidas usando polieletrólitos, tais como condensados de formaldeído sulfonato naftaleno de sódio. Ésteres de fosfato etoxilato de tristirilfenol também são usados. Não iônicos tais como condensados de óxido de alquilariletileno e copolímeros em bloco EO-PO são às vezes combinados com aniônicos como agentes dispersantes para concentrados de suspensão. Em anos recentes, novos tipos de tenso- ativos poliméricos de elevado peso molecular foram desenvolvidos como agentes dispersantes. Esses são ‘espinhas dorsais’ hidrofóbicas muito longas e um grande número de cadeias de óxido de etileno formam o ‘dente’ de um tensoativo ‘comb’ (combinação). Esses polímeros de elevado pelo molecular podem fornecer estabilidade muito bom em longo prazo para concentrados de suspensão, pois as espinhas dorsais hidrofóbicas possuem muitos pontos de ancoragem sobre as superfícies das partículas. Exemplos de agentes dispersantes usados nas formulações agroquímicas são: lignossulfatos de sódio; condensados de formaldeído sulfonato naftaleno de sódio; ésteres de fosfato etoxilato tristirilfenol; etoxilatos de álcool alifático; etoxilatos de alquila; copolímeros em bloco EO-PO; e copolímeros de enxerto.[000474] A dispersing agent is a substance that absorbs onto the surface of particles, helps to preserve the dispersed state of the particles and prevents them from regrouping. Dispersing agents are added to agrochemical formulations to facilitate dispersion and suspension during manufacture and to ensure that the particles are re-dispersed in water in a spray tank. They are widely used in wettable powders, suspension concentrates and water dispersible granules. Surfactants that are used as dispersing agents have the ability to absorb heavily onto a particle surface and provide a charged or steric barrier for particle reassembly. The most commonly used surfactants are anionic, non-ionic or mixtures of both types. For wettable powder formulations, the most common dispersing agents are sodium lignosulfonates. For suspension concentrates, very good absorption and stabilization is generally achieved using polyelectrolytes such as sodium naphthalene sulfonate formaldehyde condensates. Tristyrylphenol ethoxylate phosphate esters are also used. Nonionics such as alkylarylethylene oxide condensates and EO-PO block copolymers are sometimes combined with anionics as dispersing agents for suspension concentrates. In recent years, new types of high molecular weight polymeric surfactants have been developed as dispersing agents. These are very long hydrophobic 'backbones' and a large number of ethylene oxide chains form the 'tooth' of a 'comb' (combination) surfactant. These high molecular weight polymers can provide very good long-term stability for suspension concentrates as hydrophobic backbones have many anchor points on the particle surfaces. Examples of dispersing agents used in agrochemical formulations are: sodium lignosulfates; sodium naphthalene sulfonate formaldehyde condensates; tristyrylphenol ethoxylate phosphate esters; aliphatic alcohol ethoxylates; alkyl ethoxylates; EO-PO block copolymers; and graft copolymers.

[000475] Um agente emulsificante que estabiliza uma suspensão de gotas de uma fase líquida em outra fase líquida. Sem o agente emulsi- ficante, os dois líquidos se separariam em duas fases líquidas imiscí- veis. As misturas de emulsificantes mais comumente usadas contém um alquilfenol ou álcool alifático com doze ou mais unidades de óxido de etileno e o sal de cálcio solúvel em óleo de ácido dodecilbenzenos- sulfônico. Um intervalo de valores de equilíbrio hidrófilo-lipófilo (EHL) de cerca de 8 a cerca de 18 normalmente fornecerão boas emulsões estáveis. A estabilidade da emulsão pode às vezes ser melhorada pela adição de uma quantidade pequena de um tensoativo de copolímero em bloco EO-PO.[000475] An emulsifying agent that stabilizes a suspension of droplets from one liquid phase into another liquid phase. Without the emulsifying agent, the two liquids would separate into two immiscible liquid phases. The most commonly used emulsifier blends contain an alkylphenol or aliphatic alcohol with twelve or more ethylene oxide units and the oil-soluble calcium salt of dodecylbenzenesulfonic acid. A range of hydrophile-lipophile balance (HLB) values of about 8 to about 18 will normally provide good stable emulsions. Emulsion stability can sometimes be improved by adding a small amount of an EO-PO block copolymer surfactant.

[000476] Um agente solubilizante é um tensoativo que formará mice- las na água em concentrações acima da concentração crítica de mice- las. As micelas são capazes de dissolver ou solubilizar materiais insolúveis em água dentro da parte hidrofóbica da micela. Os tipos de ten- soativos geralmente usados para solubilização são não iônicos, mono- oletatos de sorbitano e ésteres de oleato de metila.[000476] A solubilizing agent is a surfactant that will form micelles in water in concentrations above the critical concentration of micelles. Micelles are capable of dissolving or solubilizing water insoluble materials within the hydrophobic part of the micelle. The types of surfactants commonly used for solubilization are non-ionic, sorbitan monoolelates and methyl oleate esters.

[000477] Às vezes, tensoativos são usados sozinhos ou com outros aditivos, tais como óleos minerais ou vegetais como adjuvantes para misturas em tanque de pulverização para melhorar o desempenho bio-lógico do pesticida no alvo. Os tipos de tensoativos usados para bioa- perfeiçoamento dependem geralmente da natureza e modo de atuação do pesticida. Contudo, eles são geralmente não iônicos, tais como: etoxilatos de alquila; etoxilatos de álcool alifático linear; e etoxilatos de amina alifática.[000477] Sometimes surfactants are used alone or with other additives such as mineral or vegetable oils as adjuncts to spray tank mixes to improve the biological performance of the pesticide on the target. The types of surfactants used for bio-improvement generally depend on the nature and mode of action of the pesticide. However, they are generally non-ionic, such as: alkyl ethoxylates; linear aliphatic alcohol ethoxylates; and aliphatic amine ethoxylates.

[000478] Um veículo ou diluente em uma formulação agrícola é um material adicionado ao pesticida para fornecer um produto da resistência necessária. Em geral, veículos são materiais com elevadas capacidades de absorção, enquanto que os diluentes são geralmente materiais com baixas capacidades de absorção. Veículos e diluentes são usados nas formulações de pós, pós molháveis, grânulos e grânulos dispersíveis em água.[000478] A vehicle or diluent in an agricultural formulation is a material added to the pesticide to provide a product of the required strength. In general, vehicles are materials with high absorptive capacities, whereas diluents are generally materials with low absorptive capacities. Vehicles and diluents are used in the formulation of powders, wettable powders, granules and water dispersible granules.

[000479] Solventes orgânicos são usados principalmente na formulação de concentrados emulsificáveis, emulsões óleo em água, suspoe- mulsões, dispersões em óleo e formulações de ultra baixo volume e, em uma menor extensão, formulações granulares. Não é raro serem usadas misturas de solventes. Os primeiros grupos principais de solventes são óleos parafínicos alifáticos, tais como querosene e parafinas refinadas. O segundo grupo principal (e o mais comum) compre- ende os solventes aromáticos, tais como xileno e frações de elevado peso molecular de C9 e solventes aromáticos de C10. Hidrocarbone- tos clorados são úteis como co-solventes para evitar a cristalização de pesticidas quando a formulação é emulsificada em água. Eventualmente, álcoois são usados como co-solventes para aumentar o pó de solvente. Outros solventes podem incluir óleos vegetais, óleos de sementes e ésteres de vegetais e óleos de sementes.[000479] Organic solvents are mainly used in the formulation of emulsifiable concentrates, oil-in-water emulsions, suspoemulsions, oil dispersions and ultra low volume formulations and, to a lesser extent, granular formulations. It is not uncommon to use mixtures of solvents. The first major groups of solvents are aliphatic paraffinic oils such as kerosene and refined paraffins. The second main (and most common) group comprises aromatic solvents such as xylene and high molecular weight fractions of C9 and aromatic solvents of C10. Chlorinated hydrocarbons are useful as co-solvents to prevent pesticide crystallization when the formulation is emulsified in water. Eventually, alcohols are used as co-solvents to increase the solvent powder. Other solvents can include vegetable oils, seed oils and vegetable esters and seed oils.

[000480] Agentes espessantes ou gelificantes são usados principalmente na formulação de concentrados de suspensão, dispersões em óleo, emulsões e suspoemulsões para modificar a reologia das propriedades de fluxo do líquido e para evitar a separação e sedimentação das partículas e gotas dispersas. Agentes espessantes, gelificantes e antissedimentação geralmente se encaixam em duas categorias, ou seja, particulado insolúvel em água e polímeros solúveis em água. É possível produzir concentrado de suspensão e formulações de dispersão em óleo usando argilas e sílicas. Exemplos desses tipos de materiais incluem, mas não se limitam a, montomorillonita, bentonita, silica- to de magnésio e alumínio e atapulgita. Polissacarídeos solúveis em água em concentrados de suspensão baseados em água foram usados como agentes espessantes-gelificantes durante muitos anos. Os tipos de polissacarídeos mais comumente usados são extratos naturais de sementes e algas marinhas ou são derivados sintéticos de celulose. Exemplos desses tipos de materiais incluem, mas não se limitam a, goma guar; goma de alfarroba; carragenina; alginatos; metil celulose; carbóximetilcelulose de sódio (SCMC); e hidroetilcelulose (HEC). Outros tipos de agentes anti-sedimentação são baseados em amidos modificados, poliacrilatos, álcool polivinílico e óxido de polietileno. Outro bom agente anti-sedimentação é goma xantana.[000480] Thickening or gelling agents are mainly used in the formulation of suspension concentrates, oil dispersions, emulsions and suspoemulsions to modify the rheology of liquid flow properties and to prevent separation and sedimentation of the dispersed particles and droplets. Thickening, gelling and anti-settling agents generally fall into two categories, namely, water-insoluble particulates and water-soluble polymers. It is possible to produce suspension concentrate and oil dispersion formulations using clays and silicas. Examples of these types of materials include, but are not limited to, montomorillonite, bentonite, magnesium aluminum silicate, and attapulgite. Water-soluble polysaccharides in water-based suspension concentrates have been used as thickening-gelling agents for many years. The most commonly used types of polysaccharides are natural extracts from seeds and seaweed or are synthetic cellulose derivatives. Examples of these types of materials include, but are not limited to, guar gum; locust bean gum; carrageenan; alginates; methyl cellulose; sodium carboxymethylcellulose (SCMC); and hydroethylcellulose (HEC). Other types of anti-settling agents are based on modified starches, polyacrylates, polyvinyl alcohol and polyethylene oxide. Another good anti-sedimentation agent is xanthan gum.

[000481] Micro-organismos podem provocar deterioração dos produtos formulados. Portanto, agentes conservantes são usados para eli- minar ou reduzir os seus efeitos. Exemplos desses agentes incluem, mas não se limitam a: ácido propiônico e seu sal de sódio; ácido sórbi- co e seus sais de sódio ou potássio; ácido benzoico e seu sal de sódio; sal de sódio de ácido p- hidróxibenzoico; p- hidróxibenzoato de metila; e 1,2-benzisotiazolina-3-um (BIT).[000481] Micro-organisms can cause deterioration of formulated products. Therefore, preservative agents are used to eliminate or reduce its effects. Examples of such agents include, but are not limited to: propionic acid and its sodium salt; sorbic acid and its sodium or potassium salts; benzoic acid and its sodium salt; p-hydroxybenzoic acid sodium salt; methyl p-hydroxybenzoate; and 1,2-benzisothiazoline-3-one (BIT).

[000482] A presença de tensoativos geralmente faz com que formulações à base de água forem espuma durante as operações de mistura na produção e aplicação através de um tanque de pulverização. A fim de reduzir a tendência para formar espuma, agentes antiespuman- tes são geralmente adicionados durante o estágio de produção ou antes do preenchimento dos recipientes. Geralmente, existem dois tipos de agentes antiespumante, ou seja, silicones e não silicones. Silicones são usualmente emulsões aquosas de polissiloxano de dimetila, enquanto que agentes antiespumantes não silicone são óleos insolúveis em água, tais como octanol e nonanol, ou sílica. Em ambos os casos, a função do agente antiespumante é deslocar o tensoativo a partir da interface ar-água.[000482] The presence of surfactants generally causes water-based formulations to foam during mixing operations in production and application through a spray tank. In order to reduce the tendency to foam, defoamers are usually added during the production stage or before filling the containers. Generally, there are two types of defoamers, namely silicones and non-silicones. Silicones are usually aqueous dimethyl polysiloxane emulsions, while non-silicone defoamers are water-insoluble oils, such as octanol and nonanol, or silica. In both cases, the function of the defoamer is to displace the surfactant from the air-water interface.

[000483] Agentes "verdes" (por exemplo., adjuvantes, tensoativos, solventes) podem produzir a pegada ambiental geral de formulações de proteção de cultivos. Agentes verdes são biodegradáveis e geralmente derivados de fontes naturais e/ou sustentáveis, por exemplo, fontes de plantes e animais. Exemplos específicos são: óleos vegetais, óleos de sementes e ésteres dos mesmos, bem como poliglicosídeos de alquila alcoxilada.[000483] "Green" agents (eg adjuvants, surfactants, solvents) can produce the overall environmental footprint of crop protection formulations. Green agents are biodegradable and generally derived from natural and/or sustainable sources, eg plant and animal sources. Specific examples are: vegetable oils, seed oils and esters thereof, as well as alkyl alkoxylated polyglycosides.

Aplicaçõesapplications

[000484] Moléculas da Fórmula Um podem ser aplicadas em qualquer lócus. Os loci particulares para aplicar tais moléculas incluem loci onde alfafa, amêndoas, maçãs, cevada, feijão, canola, milho, algodão, crucíferos, flores, espécies de forragem (Lólio, Erva do Sudão, Festuca Alta, Erva de Febra e Trevo), frutas, alface, aveia, oleaginosas, laran- jas, amendoim, peras, pimentas, batatas, arroz, sorgo, soja, morangos, cana-de-açúcar, beterrabas, girassóis, tabaco, tomate, trigo (por exemplo, Trigo Duro e Vermelho de Inverno, Trigo Mole e Vermelho de Inverno, Trigo Branco de Inverno, Trigo Duro e Vermelho de Primavera e Trigo Durum (Duro) de Primavera), e outros valiosos cultivos estão crescendo ou as sementes deles serão plantadas.[000484] Formula One molecules can be applied at any locus. Particular loci for applying such molecules include loci where alfalfa, almonds, apples, barley, beans, canola, corn, cotton, cruciferous, flowers, forage species (Lollium, Sudan Herb, Festuca Alta, Febra Grass and Clover), fruits, lettuce, oats, oilseeds, oranges, peanuts, pears, peppers, potatoes, rice, sorghum, soybeans, strawberries, sugar cane, beets, sunflowers, tobacco, tomatoes, wheat (eg Durum Wheat and Winter Red, Soft and Winter Red, Winter White Wheat, Hard and Spring Red and Spring Durum (Hard) Wheat), and other valuable crops are growing or their seeds will be planted.

[000485] Moléculas da Fórmula Um também podem ser aplicadas onde plantas, tais como cultivos, estão crescendo e onde existem níveis baixos (mesmo sem presença real) de pragas que podem danificar comercialmente estas plantas. Aplicar as referidas moléculas nesses lócus é benéfico para as plantas que crescem nesses lócus. Os benefícios citados podem incluir, mas não se limitam a: ajudar a planta a desenvolver um sistema de enraizamento melhor; ajudar a planta a resistir melhor às crescentes condições de estresse; melhorar a saúde de uma planta; melhorar o rendimento de uma planta(por exemplo, maior biomassa e/ou maior teor de ingredientes valiosos); melhorar o vigor da planta (por exemplo, melhor crescimento da planta e/ou folhas mais verdes); melhorar a qualidade de uma planta (por exemplo, melhor teor ou composição de determinados ingredientes); e melhorar a tolerância ao estresse abiótico e/ou biótico da planta.[000485] Formula One molecules can also be applied where plants, such as crops, are growing and where there are low levels (even without actual presence) of pests that can commercially damage these plants. Applying said molecules at these loci is beneficial for plants growing at these loci. The benefits cited may include, but are not limited to: helping the plant develop a better rooting system; help the plant better resist increasing stress conditions; improve the health of a plant; improve a plant's yield (eg higher biomass and/or higher content of valuable ingredients); improve plant vigor (eg better plant growth and/or greener leaves); improve the quality of a plant (for example, better content or composition of certain ingredients); and improve the plant's abiotic and/or biotic stress tolerance.

[000486] Moléculas da Fórmula Um podem ser aplicadas com sulfato de amônio ao cultivar várias plantas, pois isto pode fornecer benefícios adicionais.[000486] Formula One molecules can be applied with ammonium sulfate when cultivating various plants as this can provide additional benefits.

[000487] Moléculas da Fórmula Um podem ser aplicadas sobre, dentro ou entorno de plantas geneticamente modificadas para expressar traços especializados, tais como Bacillus thuringiensis (por exemplo, Cry1Ab, Cry1Ac, Cry1Fa, Cry1A.105, Cry2Ab, Vip3A, mCry3A, Cry3Ab, Cry3Bb, Cry34Ab1/Cry35Ab1), outras toxinas inseticidas e aquelas que expressam tolerância à herbicida ou aquelas com genes estranhos "empilhados" que expressam toxinas inseticidas, tolerância a herbicidas, aprimoramento em nutrição e outros traços benéficos.[000487] Molecules of Formula One can be applied on, within or around genetically modified plants to express specialized traits such as Bacillus thuringiensis (for example, Cry1Ab, Cry1Ac, Cry1Fa, Cry1A.105, Cry2Ab, Vip3A, mCry3A, Cry3Ab, Cry3Bb, Cry34Ab1/Cry35Ab1), other insecticidal toxins, and those expressing herbicide tolerance or those with "stacked" foreign genes expressing insecticidal toxins, herbicide tolerance, improved nutrition, and other beneficial traits.

[000488] Moléculas da Fórmula Um podem ser aplicadas em porções foliares e/ou frutíferas de plantas para controlar pragas. Essas moléculas entrarão em contato direto com a praga ou a praga consumirá essas moléculas ao se alimentar da planta ou enquanto extrai a seiva ou outros nutrientes da planta.[000488] Formula One molecules can be applied to foliar and/or fruiting portions of plants to control pests. These molecules will either come into direct contact with the pest or the pest will consume these molecules when feeding on the plant or while extracting sap or other nutrients from the plant.

[000489] Moléculas da Fórmula Um também podem ser aplicadas no solo e, quando aplicadas dessa forma, as pragas que se alimentam de raízes e caules podem ser controladas. As raízes podem absorver essas moléculas por conduzi-las até as porções foliares da planta para controlar pragas mastigadoras superiores e pragas que se alimentam de seiva.[000489] Formula One molecules can also be applied to the soil and, when applied in this way, root and stem feeding pests can be controlled. The roots can absorb these molecules by carrying them to the foliar portions of the plant to control superior chewing pests and sap-feeding pests.

[000490] O movimento sistêmico dos pesticidas em plantas pode ser utilizado para controlar pragas em uma porção da planta ao aplicar (por exemplo, ao pulverizar um lócus) uma molécula da Fórmula Um em uma porção diferente da planta. Por exemplo, o controle de insetos que se alimentam de folhas pode ser obtido pela irrigação por goteja- mento ou aplicação em sulcos, pelo tratamento do solo com, por exemplo, encharcamento do solo pré- ou pós-plantio ou por tratamento das sementes de uma planta antes do plantio.[000490] Systemic movement of pesticides into plants can be used to control pests in a portion of the plant by applying (eg by spraying a locus) a molecule of Formula One to a different portion of the plant. For example, control of leaf-feeding insects can be achieved by drip irrigation or application in furrows, by treating the soil with, for example, pre- or post-planting soil waterlogging, or by treating the seeds. a plant before planting.

[000491] Moléculas da Fórmula Um podem ser usadas como iscas. Geralmente, com uso de iscas, as mesmas são colocadas no solo onde, por exemplo, cupins podem entrar em contato e/ou serem atraídos à isca. Iscas também podem ser aplicadas em uma superfície de uma construção (horizontal, vertical ou superfície inclinada) onde, por exemplo, formigas, cupins, baratas e moscas entram em contato e/ou são atraídas à isca.[000491] Formula One molecules can be used as baits. Generally, with the use of baits, they are placed on the ground where, for example, termites can come into contact and/or be attracted to the bait. Bait can also be applied to a building surface (horizontal, vertical or sloped surface) where, for example, ants, termites, cockroaches and flies come into contact and/or are attracted to the bait.

[000492] Moléculas da Fórmula Um podem ser encapsuladas dentro ou colocadas sobre a superfície de uma cápsula. O tamanho das cápsulas pode variar de tamanho nanométrico (cerca de 100-900 nanô- metros em diâmetro) a tamanho micrométrico (cerca de 10-900 micra em diâmetro).[000492] Formula One molecules can be encapsulated within or placed on the surface of a capsule. The size of capsules can range from nanometer size (about 100-900 nanometers in diameter) to micrometer size (about 10-900 micrometers in diameter).

[000493] Moléculas da Fórmula Um podem ser aplicadas em ovos de pragas. Em vista da capacidade única que os ovos de algumas pestes possuem para resistir a determinados pesticidas, aplicações repetidas dessas moléculas podem ser desejáveis para controlar larvas que acabaram de eclodir.[000493] Formula One molecules can be applied to pest eggs. In view of the unique ability of some pest eggs to resist certain pesticides, repeated applications of these molecules may be desirable to control newly hatched larvae.

[000494] Moléculas da Fórmula Um podem ser aplicadas como tra-tamentos de sementes. O tratamento de sementes pode ser aplicado em todos os tipos de sementes, incluindo aquelas nas quais as plantas são geneticamente modificadas para expressar traços especializados as quais germinarão. Exemplos representativos incluem aquelas que expressam proteínas tóxicas para pragas de invertebrados, tais como Bacillus thuringiensis ou outras toxinas inseticidas, aquelas que ex-pressam tolerância à herbicida, tais como semente de "Roundup Ready" ou aquelas com genes estranhos "empilhados" que expressam toxinas inseticidas, tolerância a herbicidas, aprimoramento de nutrição, tolerância a enchentes ou qualquer outro traço benéfico. Além disso, esses tratamentos de sementes com moléculas da Fórmula Um podem ainda aprimorar a capacidade de uma planta para resistir melhor a crescentes condições de estresse. Isso resulta em uma planta mais saudável e vigorosa que pode levar a maiores rendimentos no tempo de colheita. Em geral, cerca de 1 grama dessas moléculas a cerca de 500 gramas por 100.000 sementes é esperado que forneça bons benefícios, quantidades de cerca de 10 gramas a cerca de 100 gramas por 100.000 sementes é esperado que forneça benefícios melhores e quantidades de cerca de 25 gramas a cerca de 75 gramas por 100.000 sementes é esperado que forneça benefícios ainda melhores.[000494] Formula One molecules can be applied as seed treatments. Seed treatment can be applied to all types of seeds, including those in which the plants are genetically modified to express specialized traits which will germinate. Representative examples include those that express proteins toxic to invertebrate pests, such as Bacillus thuringiensis or other insecticidal toxins, those that express herbicide tolerance, such as "Roundup Ready" seed, or those with foreign "stacked" genes that express toxins insecticides, herbicide tolerance, nutrition enhancement, flood tolerance or any other beneficial trait. In addition, these seed treatments with Formula One molecules can further enhance a plant's ability to better resist increasing stress conditions. This results in a healthier and more vigorous plant that can lead to higher yields at harvest time. In general, about 1 gram of these molecules at about 500 grams per 100,000 seeds is expected to provide good benefits, amounts of about 10 grams to about 100 grams per 100,000 seeds are expected to provide better benefits, and amounts of about 25 grams at about 75 grams per 100,000 seeds is expected to provide even better benefits.

[000495] Moléculas da Fórmula Um podem ser aplicadas com um ou mais princípios ativos em um condicionador de solo.[000495] Formula One molecules can be applied with one or more active ingredients in a soil conditioner.

[000496] Moléculas da Fórmula Um podem ser usadas para controlar endoparasitas e ectoparasitas no setor de medicina veterinária ou no campo de criação de animais. Essas moléculas podem ser aplicadas por administração oral na forma de, por exemplo, comprimidos, cápsulas, bebidas, grânulos, por aplicação dérmica na forma de, por exemplo, imersão, pulverização, verter em, marcação em e polvilhamento, e por administração parenteral na forma de, por exemplo, uma injeção.[000496] Formula One molecules can be used to control endoparasites and ectoparasites in the veterinary medicine sector or in the animal husbandry field. Such molecules can be applied by oral administration in the form of, for example, tablets, capsules, beverages, granules, by dermal application in the form of, for example, dipping, spraying, pouring in, labeling and dusting, and by parenteral administration in the form of, for example, an injection.

[000497] Moléculas da Fórmula Um também podem ser empregadas vantajosamente na criação de animais de fazenda, por exemplo, gado, galinhas, ganso, cabras, porcos, ovelhas e perus. Elas também podem ser empregadas vantajosamente em animais domésticos, tais como cavalos, cães e gatos. Pragas específicas que devem ser controladas incluiriam moscas, pulgas e carrapatos que são incomodativos para os referidos animais. Formulações adequadas são administradas oralmente aos animais com água potável ou alimentação. As dosagens e formulações que são adequadas depende da espécie.[000497] Formula One molecules can also be used to advantage in raising farm animals, eg cattle, chickens, goose, goats, pigs, sheep and turkeys. They can also be used to advantage in domestic animals such as horses, dogs and cats. Specific pests that must be controlled would include flies, fleas and ticks that are annoyance to said animals. Suitable formulations are administered orally to animals with drinking water or food. The dosages and formulations that are suitable depend on the species.

[000498] Moléculas da Fórmula Um também podem ser usadas para controlar vermes parasitas, especialmente do intestino, nos animais listados anteriormente.[000498] Formula One molecules can also be used to control parasitic worms, especially of the intestine, in the animals listed above.

[000499] Moléculas da Fórmula Um também podem ser empregadas em métodos terapêuticos para cuidados em saúde humana. Esses métodos incluem, mas não se limitam a, administração oral na forma de, por exemplo, comprimidos, cápsulas, bebidas, grânulos e por aplicação dérmica.[000499] Formula One molecules can also be employed in therapeutic methods for human health care. Such methods include, but are not limited to, oral administration in the form of, for example, tablets, capsules, beverages, granules and by dermal application.

[000500] Moléculas da Fórmula Um também podem ser aplicadas em pragas invasoras. Pragas em todo o mundo migraram para ambientes novos (para as referidas pragas) e, portanto, se tornam uma nova espécie invasora no referido ambiente novo. Essas moléculas também podem ser usadas na referida nova espécie invasora para controlá-las nos ambientes novos.[000500] Formula One molecules can also be applied to invasive pests. Pests all over the world have migrated to new environments (for those pests) and therefore become a new invasive species in said new environment. These molecules can also be used in said new invasive species to control them in new environments.

[000501] Antes de um pesticida poder ser utilizado ou vendido co-mercialmente, o mesmo é submetido a longos processos de avaliações por várias autoridades governamentais (locais, regionais, estaduais, nacionais e internacionais). As autoridades reguladoras especificam extensas exigências de dados que devem ser tratadas através da geração e envio de informações pelo requerente de registro do produto ou por um terceiro a favor do requerente de registro do produto, geralmente utilizando um computador com uma conexão à rede mundial de computadores. Essas autoridades governamentais analisam as in-formações e, caso seja concluída uma determinação de segurança, fornecem ao potencial usuário ou vendedor a aprovação de registro do produto. Portanto, na localidade onde o registro do produto é concedida e suportada, o referido usuário ou vendedor pode usar ou vender o pesticida.[000501] Before a pesticide can be used or sold commercially, it is subjected to lengthy evaluation processes by various government authorities (local, regional, state, national and international). Regulatory authorities specify extensive data requirements that must be handled through the generation and submission of information by the applicant for product registration or by a third party on behalf of the applicant for product registration, usually using a computer with a connection to the world wide web . These government authorities review the information and, if a safety determination is completed, provide the potential user or seller with approval to register the product. Therefore, in the locality where product registration is granted and supported, said user or seller may use or sell the pesticide.

[000502] Moléculas de acordo com a Fórmula Um podem ser testadas para determinar a eficácia contra pragas. Além disso, podem ser conduzidos estudos de mecanismo de ação para determinar se a referida molécula possui um mecanismo de ação diferente dos outros pesticidas. Posteriormente, essas informações obtidas podem ser disseminadas, tais como pela internet, a terceiros.[000502] Molecules according to Formula One can be tested to determine effectiveness against pests. In addition, mechanism of action studies can be conducted to determine whether said molecule has a different mechanism of action than other pesticides. Subsequently, this information obtained may be disseminated, such as over the internet, to third parties.

[000503] Como consequência, em luz do acima exposto, e das Tabelas na Seção de Tabelas, são fornecidos os seguintes detalhes (D) adicionais e não abrangentes.1D. Uma molécula com a seguinte fórmula

Figure img0325
em que:(A) R1 é selecionado do grupo consistindo em H, F, Cl,Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4) alqueni- la, (C3-C6)cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4)haloal- quila, (C3-C6)halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halocicloal- quenila, (C1-C4)haloalcóxi, S(C1-C4)alquila, S(O)(C1-C4)alquila, S(O)2 (C1-C4)alquila, S(C1-C4)haloalquila, S(O)(C1-C4)haloalquila, S(O)2(C1-C4) haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil-S(O)2NH2;(B) R2 é selecionado do grupo consistindo em H, F, Cl,Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4)alque- nila, (C3-C6)cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4)halo- alquila, (C3-C6)halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halociclo- alquenila, (C1-C4)haloalcóxi, S(C1-C4)alquila, S(O)(C1-C4)alquila, S(O)2 (C1-C4)alquila, S(C1-C4)haloalquila, S(O)(C1-C4)haloalquila, S(O)2(C1- C4)haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil-S(O)2NH2;(C) R3 é selecionado do grupo consistindo em H, F, Cl,Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4)al- quenila, (C3-C6)cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4) haloalquila, (C3-C6)halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halo- cicloalquenila, (C1-C4)haloalcóxi, S(C1-C4)alquila, S(O)(C1-C4)alquila, S(O)2(C1-C4)alquila, S(C1-C4)haloalquila, S(O)(C1-C4)haloalquila, S(O)2 (C1-C4)haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil-S(O)2 NH2;(D) R4 é selecionado do grupo consistindo em H, F, Cl,Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4) alqueni- la, (C3-C6)cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4)haloal- quila, (C3-C6)halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halocicloal- quenila, (C1-C4)haloalcóxi, S(C1-C4)alquila, S(O)(C1-C4)alquila, S(O)2 (C1-C4)alquila, S(C1-C4)haloalquila, S(O)(C1-C4)haloalquila, S(O)2(C1- C4)haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil-S(O)2NH2; (E) R5 é selecionado do grupo consistindo em H, F, Cl,Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4)alquenila, (C3-C6)cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4) haloalquila, (C3-C6)halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halocicloalquenila, (C1-C4)haloalcóxi, S(C1-C4)alquila, S(O)(C1-C4)alquila, S(O)2(C1- C4)alquila, S(C1-C4)haloalquila, S(O)(C1-C4)haloalquila, S(O)2 (C1- C4)haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil-S(O)2 NH2;(F) R6 é selecionado do grupo consistindo em H e (C1-C4)alquil;(G) R7 é selecionado do grupo consistindo em H, F, Cl,Br e I;(H) R8 é selecionado do grupo consistindo em F, Cl, Br, I;(I) R9 é selecionado do grupo consistindo em H e (C1-C4)alquil;(J) R10 é selecionado do grupo consistindo em H, (C1-C4)alquila, (C2-C4)alquenila, (C1-C4)haloalquila, (C1-C4)alquil(C1-C4)alcóxi, C(=O)(C1-C4)alquil e (C1-C4)alcóxiC(=O)(C1-C4)alquil;(K) R11 é selecionado do grupo consistindo em H, F, Cl,Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4) alqueni- la, (C3-C6)cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4)haloal- quila, (C3-C6)halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halocicloal- quenila, (C1-C4)haloalcóxi, S(C1-C4)alquila, S(O)(C1-C4)alquila, S(O)2 (C1-C4)alquila, S(C1-C4)haloalquila, S(O)(C1-C4)haloalquila, S(O)2(C1-C4) haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil-S(O)2NH2;(L) R12 é selecionado do grupo consistindo em H, F, Cl,Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4)alque- nila, (C3-C6)cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4)halo- alquila, (C3-C6)halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halociclo- alquenila, (C1-C4)haloalcóxi, S(C1-C4)alquila, S(O)(C1-C4)alquila, S(O)2 (C1-C4)alquila, S(C1-C4)haloalquila, S(O)(C1-C4)haloalquila, S(O)2(C1-C4) haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil-S(O)2NH2;(M) R13 é selecionado do grupo consistindo em H, F, Cl,Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4)alque- nila, (C3-C6)cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4)halo- alquila, (C3-C6)halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halociclo- alquenila, (C1-C4)haloalcóxi, S(C1-C4)alquila, S(O)(C1-C4)alquila, S(O)2 (C1-C4)alquila, S(C1-C4)haloalquila, S(O)(C1-C4)haloalquila, S(O)2(C1-C4) haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil-S(O)2NH2;(N) R14 é selecionado do grupo consistindo em H, F, Cl,Br, I, CN, NH2, NO2, (C1-C4)alquila, (C3-C6)cicloalquila, (C2-C4)alque- nila, (C3-C6)cicloalquenila, (C2-C4)alquinila, (C1-C4)alcóxi, (C1-C4)halo- alquila, (C3-C6)halocicloalquila, (C2-C4)haloalquenila, (C3-C6)halociclo- alquenila, (C1-C4)haloalcóxi, S(C1-C4)alquila, S(O)(C1-C4)alquila, S(O)2 (C1-C4)alquila, S(C1-C4)haloalquila, S(O)(C1-C4)haloalquila, S(O)2(C1-C4) haloalquila, (C1-C4)alquil-S(O)2NH2 e (C1-C4)haloalquil-S(O)2NH2;(O) R15 é selecionado do grupo consistindo em H, (C1-C4)alquila, (C2-C4)alquenila, (C1-C4)haloalquila, (C1-C4)alquil(C1-C4)alcóxi, C(=O)(C1-C4)alquil e (C1-C4)alcóxiC(=O)(C1-C4)alquil;(P) R16 é selecionado do grupo consistindo em (C3-C8)cicloalquila, azetidinila, 2,5-dioxoimidazolidinila, 2,4-dioxo-1,3-diazas- piro[4,4]nonanilisoxazolidinonila, imidazolidinonila, isoxazolidinonila, morfolinila, oxazolidinonila, oxetanila, piperazinila, piperidinila, piranila, pirrolidinila, pirrolidinonila, tetra-hidrofuranila, tetra-hidropiranila, tetra- hidrotiofenila, tetra-hidrotiofenil-óxido, tetra-hidrotiofenil-dióxido, tietani- la, tietanil-óxido, tietanil-dióxido, e tioxotiazolidinonila, em que cada cicloalquila, azetidinila, 2,5-dioxoimidazolidinila, 2,4-dioxo-1,3-diazas- piro[4,4]nonanilisoxazolidinonila, imidazolidinonila, isoxazolidinonila, morfolinila, oxazolidinonila, oxetanila, piperazinila, piperidinila, piranila, pirrolidinila, pirrolidinonila, tetra-hidrofuranila, tetra-hidropiranila, tetra- hidrotiofenila, tetra-hidrotiofenil-óxido, tetra-hidrotiofenil-dióxido, tietani- la, tietanil-óxido, tietanil-dióxido, e tioxotiazolidinonil pode ser opcio-nalmente substituído por um ou mais substituintes selecionados dentre H, F, Cl, Br, I, CN, NH2, NO2, oxo, (C1-C4)alquila, (C1-C4)haloalquila, C(=O)O(C1-C4)alquila, (C=O)NH(C1-C4)alquila, (C=O)NH(C1-C4)haloal- quila, C(=O)(C3-C6)ciclopropila, C(=O)(C1-C4)haloalquila, C(=O)(C1-C4) alquil(C1-C4)alcóxi, e (C1-C4)alquil-morfolinil;((Q) Q1 e Q2 são, cada um, independentemente selecionados do grupo consistindo em O e S; ee N-óxidos, sais de adição de ácidos, derivados de sais, solvatos, derivados de ésteres, polimorfos cristalinos, isótopos, estere- oisômeros resolvidos e tautômeros agricolamente aceitáveis das mo-léculas da Fórmula Um.[000503] As a consequence, in light of the above, and the Tables in the Tables Section, the following additional and not comprehensive details (D) are provided.1D. A molecule with the following formula
Figure img0325
wherein: (A) R 1 is selected from the group consisting of H, F, Cl, Br, I, CN, NH 2 , NO 2 , (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 4 ) alkenyl. la, (C3-C6)cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C3-C6)halocycloalkyl, (C2-C4)haloalkenyl, (C3-C6 )halocycloalkenyl, (C1-C4)haloalkoxy, S(C1-C4)alkyl, S(O)(C1-C4)alkyl, S(O)2(C1-C4)alkyl, S(C1-C4)haloalkyl , S(O)(C1-C4)haloalkyl, S(O)2(C1-C4)haloalkyl, (C1-C4)alkyl-S(O)2NH2 and (C1-C4)haloalkyl-S(O)2NH2; (B) R2 is selected from the group consisting of H, F, Cl,Br, I, CN, NH2, NO2, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C2-C4)alkenyl, ( C3-C6)cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C3-C6)halocycloalkyl, (C2-C4)haloalkenyl, (C3-C6)halocyclo- alkenyl, (C1-C4)haloalkoxy, S(C1-C4)alkyl, S(O)(C1-C4)alkyl, S(O)2(C1-C4)alkyl, S(C1-C4)haloalkyl, S( O)(C1-C4)haloalkyl, S(O)2(C1-C4)haloalkyl, (C1-C4)alkyl-S(O)2NH2 and (C1-C4)haloalkyl-S(O)2NH2;(C) R3 is selected from the group consisting of H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C2-C4)alkenyl, (C3-C6)cycloalkenyl , (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4) haloalkyl, (C3-C6)halocycloalkyl, (C2-C4)haloalkenyl, (C3-C6)halocycloalkenyl, (C1-C4) haloalkoxy, S(C1-C4)alkyl, S(O)(C1-C4)alkyl, S(O)2(C1-C4)alkyl, S(C1-C4)haloalkyl, S(O)(C1-C4) haloalkyl, S(O)2 (C1-C4)haloalkyl, (C1-C4)alkyl-S(O)2NH2 and (C1-C4)haloalkyl-S(O)2 NH2; (D) R4 is selected from the group consisting of in H, F, Cl,Br, I, CN, NH2, NO2, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C2-C4) alkenyl, (C3-C6)cycloalkenyl, (C2- C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C3-C6)halocycloalkyl, (C2-C4)haloalkenyl, (C3-C6)halocycloalkenyl, (C1-C4)haloalkoxy, S(C1-C4)alkyl, S(O)(C1-C4)alkyl, S(O)2(C1-C4)alkyl, S(C1-C4)haloalkyl, S(O)(C1-C4)haloalkyl, S(O)2(C1-C4)haloalkyl, (C1-C4)alkyl-S(O)2NH2 and (C1-C4)haloalkyl-S(O)2NH2; (E) R5 is selected from the group consisting of H, F, Cl,Br, I, CN, NH2, NO2, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C2-C4)alkenyl, (C3- C6)cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4) haloalkyl, (C3-C6)halocycloalkyl, (C2-C4)haloalkenyl, (C3-C6)halocycloalkenyl, (C1-C4 )haloalkoxy, S(C1-C4)alkyl, S(O)(C1-C4)alkyl, S(O)2(C1-C4)alkyl, S(C1-C4)haloalkyl, S(O)(C1-C4 )haloalkyl, S(O)2 (C1-C4)haloalkyl, (C1-C4)alkyl-S(O)2NH2 and (C1-C4)haloalkyl-S(O)2 NH2; (F) R6 is selected from the group consisting of H and (C1-C4)alkyl; (G) R7 is selected from the group consisting of H, F, Cl,Br and I;(H) R8 is selected from the group consisting of F, Cl, Br, I;( I) R9 is selected from the group consisting of H and (C1-C4)alkyl; (J) R10 is selected from the group consisting of H, (C1-C4)alkyl, (C2-C4)alkenyl, (C1-C4)haloalkyl , (C1-C4)alkyl(C1-C4)alkoxy, C(=O)(C1-C4)alkyl and (C1-C4)alkoxyC(=O)(C1-C4)alkyl; (K) R11 is selected from group consisting of H, F, Cl, Br, I, CN, NH2, NO2, (C1-C4)alky yl, (C3-C6)cycloalkyl, (C2-C4) alkenyl, (C3-C6)cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C3 -C6)halocycloalkyl, (C2-C4)haloalkenyl, (C3-C6)halocycloalkenyl, (C1-C4)haloalkoxy, S(C1-C4)alkyl, S(O)(C1-C4)alkyl, S(O )2(C1-C4)alkyl, S(C1-C4)haloalkyl, S(O)(C1-C4)haloalkyl, S(O)2(C1-C4) haloalkyl, (C1-C4)alkyl-S(O )2NH2 and (C1-C4)haloalkyl-S(O)2NH2;(L)R12 is selected from the group consisting of H, F, Cl,Br, I, CN, NH2, NO2, (C1-C4)alkyl, ( C3-C6)cycloalkyl, (C2-C4)alkenyl, (C3-C6)cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C3-C6) halocycloalkyl, (C2-C4)haloalkenyl, (C3-C6)halocycloalkenyl, (C1-C4)haloalkoxy, S(C1-C4)alkyl, S(O)(C1-C4)alkyl, S(O)2 ( C1-C4)alkyl, S(C1-C4)haloalkyl, S(O)(C1-C4)haloalkyl, S(O)2(C1-C4) haloalkyl, (C1-C4)alkyl-S(O)2NH2 and (C1-C4)haloalkyl-S(O)2NH2;(M)R13 is selected from the group consisting of H, F, Cl,Br, I, CN, NH2, NO2, (C1-C4)alkyl, (C3-C6 ) cycloalkyl a, (C2-C4)alkenyl, (C3-C6)cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C3-C6)halocycloalkyl, (C2 -C4)haloalkenyl, (C3-C6)halocycloalkenyl, (C1-C4)haloalkoxy, S(C1-C4)alkyl, S(O)(C1-C4)alkyl, S(O)2 (C1-C4) alkyl, S(C1-C4)haloalkyl, S(O)(C1-C4)haloalkyl, S(O)2(C1-C4) haloalkyl, (C1-C4)alkyl-S(O)2NH2 and (C1-C4) )haloalkyl-S(O)2NH2;(N)R14 is selected from the group consisting of H, F, Cl,Br, I, CN, NH2, NO2, (C1-C4)alkyl, (C3-C6)cycloalkyl, ( C2-C4)alkenyl, (C3-C6)cycloalkenyl, (C2-C4)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C3-C6)halocycloalkyl, (C2-C4) haloalkenyl, (C3-C6)halocycloalkenyl, (C1-C4)haloalkoxy, S(C1-C4)alkyl, S(O)(C1-C4)alkyl, S(O)2(C1-C4)alkyl, S (C1-C4)haloalkyl, S(O)(C1-C4)haloalkyl, S(O)2(C1-C4) haloalkyl, (C1-C4)alkyl-S(O)2NH2 and (C1-C4)haloalkyl- S(O)2NH2;(O)R15 is selected from the group consisting of H, (C1-C4)alkyl, (C2-C4)alkenyl, (C1-C4)haloalkyl, (C1-C4)alkyl(C1-C4) alkoxy, C(= O)(C1-C4)alkyl and (C1-C4)alkoxyC(=O)(C1-C4)alkyl;(P)R16 is selected from the group consisting of (C3-C8)cycloalkyl, azetidinyl, 2,5-dioxoimidazolidinyl , 2,4-dioxo-1,3-diazas-pyro[4,4]nonanilisoxazolidinonyl, imidazolidinonyl, isoxazolidinonyl, morpholinyl, oxazolidinonyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydropyranyl, - hydrothiophenyl, tetrahydrothiophenyl-oxide, tetrahydrothiophenyl-dioxide, thiethanyl, thiethanyl-oxide, thiethanyl-dioxide, and thioxothiazolidinonyl, each cycloalkyl, azetidinyl, 2,5-dioxoimidazolidinyl, 2,4-dioxo-1 ,3-diazas-pyro[4,4]nonanilisoxazolidinonyl, imidazolidinonyl, isoxazolidinonyl, morpholinyl, oxazolidinonyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyloxide , tetrahydrothiophenyl-dioxide, thiethanyl-, thiethanyl-oxide, thiethanyl-dioxide, and thioxo thiazolidinonyl may optionally be substituted by one or more substituents selected from H, F, Cl, Br, I, CN, NH2, NO2, oxo, (C1-C4)alkyl, (C1-C4)haloalkyl, C(=O )O(C1-C4)alkyl, (C=O)NH(C1-C4)alkyl, (C=O)NH(C1-C4)haloalkyl, C(=O)(C3-C6)cyclopropyl, C (=O)(C1-C4)haloalkyl, C(=O)(C1-C4)alkyl(C1-C4)alkoxy, and (C1-C4)alkyl-morpholinyl;((Q)Q1 and Q2 are each , independently selected from the group consisting of O and S; ee N-oxides, acid addition salts, salt derivatives, solvates, ester derivatives, crystalline polymorphs, isotopes, resolved stereoisomers and agriculturally acceptable tautomers of the molecules of Formula One.

[000504] 2D.Uma molécula de acordo com detalhe 1D, em que o carboxamido e o fenil que estão ligados ao ciclopropano estão na con-figuração R,R.[000504] 2D. A molecule according to 1D detail, in which the carboxamido and the phenyl that are linked to the cyclopropane are in the R,R configuration.

[000505] 3D.Uma molécula de acordo com qualquer um dos detalhes anteriores (para clareza, 1D e 2D), em que R1 é selecionado do grupo que consiste em H, F e Cl.[000505] 3D. A molecule according to any of the above details (for clarity, 1D and 2D), wherein R1 is selected from the group consisting of H, F and Cl.

[000506] 4D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R2 é selecionado do grupo consistindo em H, F, Cl, Br, (C1-C4)alquil e (C1-C4)haloalquil.[000506] 4D. A molecule according to any of the foregoing details, wherein R2 is selected from the group consisting of H, F, Cl, Br, (C1-C4)alkyl and (C1-C4)haloalkyl.

[000507] 5D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R2 é selecionado do grupo consistindo em H, F, Br, CH3 e CF3.[000507] 5D.A molecule according to any of the above details, wherein R2 is selected from the group consisting of H, F, Br, CH3 and CF3.

[000508] 6D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R3 é selecionado do grupo consistindo em H, F, Cl (C1-C4)alquila, (C1-C4)haloalquil e (C1-C4)haloalcóxi.[000508] 6D. A molecule according to any of the foregoing details, wherein R3 is selected from the group consisting of H, F, Cl(C1-C4)alkyl, (C1-C4)haloalkyl and (C1-C4)haloalkoxy .

[000509] 7D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R3 é selecionado do grupo consistindo em H, F, Cl CH3, CF3 e OCF3.[000509] 7D. A molecule according to any of the foregoing details, wherein R3 is selected from the group consisting of H, F, Cl CH3, CF3 and OCF3.

[000510] 8D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R4 é selecionado do grupo consistindo em H, F, Cl, Br, (C1-C4)alquil e C1-C4)haloalquil.[000510] 8D. A molecule according to any of the foregoing details, wherein R4 is selected from the group consisting of H, F, Cl, Br, (C1-C4)alkyl and C1-C4)haloalkyl.

[000511] 9D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R4 é selecionado do grupo consistindo em H, F, Br, CH3 e CF3.[000511] 9D.A molecule according to any of the foregoing details, wherein R4 is selected from the group consisting of H, F, Br, CH3 and CF3.

[000512] 10D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R5 é selecionado do grupo consistindo em H, F e Cl.[000512] 10D. A molecule according to any of the above details, wherein R5 is selected from the group consisting of H, F and Cl.

[000513] 11D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R6 é H.[000513] 11D.A molecule according to any of the above details, where R6 is H.

[000514] 12D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R7 é Cl.[000514] 12D. A molecule according to any of the above details, where R7 is Cl.

[000515] 13D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R8 é Cl.[000515] 13D. A molecule according to any of the above details, where R8 is Cl.

[000516] 14D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R9 é H.[000516] 14D.A molecule according to any of the above details, where R9 is H.

[000517] 15D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R10 é H.[000517] 15D. A molecule according to any of the above details, where R10 is H.

[000518] 16D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R11 é H.[000518] 16D. A molecule according to any of the above details, where R11 is H.

[000519] 17D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R12 é H.[000519] 17D. A molecule according to any of the above details, where R12 is H.

[000520] 18D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R13 é selecionado do grupo consistindo em H, Cl e (C1-C4)haloalquil.[000520] 18D. A molecule according to any of the foregoing details, wherein R13 is selected from the group consisting of H, Cl and (C1-C4)haloalkyl.

[000521] 19D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R13 é selecionado do grupo consistindo em H, F, Cl e CF3.[000521] 19D.A molecule according to any of the foregoing details, wherein R13 is selected from the group consisting of H, F, Cl and CF3.

[000522] 20D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R14 é H.[000522] 20D. A molecule according to any of the above details, where R14 is H.

[000523] 21D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R15 é selecionado do grupo consistindo em H e (C1-C4)alquil.[000523] 21D. A molecule according to any of the foregoing details, wherein R15 is selected from the group consisting of H and (C1-C4)alkyl.

[000524] 22D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que R15 é selecionado do grupo consistindo em H e CH3.[000524] 22D. A molecule according to any of the foregoing details, wherein R15 is selected from the group consisting of H and CH3.

[000525] 23D.Uma molécula, de acordo com os detalhes anteriores, em que R16 é selecionado a partir do grupo consistindo em ciclo- propila, ciclobutila, ciclofenila, ciclo-hexila, azetidinila, morfolinila, oxetanila, piranila, tetra-hidrotiofenila, tietanila, tietanil-óxido e tietanil- dióxido, em que cada ciclopropila, ciclobutila, ciclopentila, ciclo-hexila, azetidinila, morfolinila, oxetanila, piranila, tetra-hidrotiofenila, tietanila, tietanil-óxido e tietanil-dióxido podem ser opcionalmente substituídos por um ou mais substituintes selecionados a partir do grupo consistindo em H, F, CN, C(=O)OC(CH3)3, e C(=O)CF3.[000525] 23D. A molecule, according to the above details, wherein R16 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclophenyl, cyclohexyl, azetidinyl, morpholinyl, oxetanyl, pyranyl, tetrahydrothiophenyl, tietanyl, tietanyl-oxide and tietanyl-dioxide, wherein each cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, morpholinyl, oxetanyl, pyranyl, tetrahydrothiophenyl, tiethanyl, tietanyl-oxide and tiethanyl-dioxide may be optionally substituted by a or more substituents selected from the group consisting of H, F, CN, C(=O)OC(CH3)3, and C(=O)CF3.

[000526] 24D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que Q1 é O.[000526] 24D.A molecule according to any of the above details, where Q1 is O.

[000527] 25D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que Q2 é O.[000527] 25D.A molecule according to any of the above details, where Q2 is O.

[000528] 26D.Uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida molécula é selecionada a partir de moléculas na Tabela 2 e Tabela P1.[000528] 26D. A molecule according to any of the above details, wherein said molecule is selected from molecules in Table 2 and Table P1.

[000529] 27D.Uma molécula, de acordo com qualquer um dos detalhes anteriores, em que a referida molécula é selecionada dentre moléculas F1 a F92, PF1 a PF9, PF12, PF14, PF18 a PF23, PF28 a PF34, PF36, PF37 e PF41 a PF45, na Tabela 2.[000529] 27D. A molecule, according to any of the above details, in which said molecule is selected from molecules F1 to F92, PF1 to PF9, PF12, PF14, PF18 to PF23, PF28 to PF34, PF36, PF37 and PF41 to PF45, in Table 2.

[000530] 28D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores relacionados às moléculas (para clareza, 1D a 27D, denominados "detalhes de molécula") compreendendo ainda um veículo.[000530] 28D. A composition comprising a molecule according to any of the foregoing details relating to molecules (for clarity, 1D to 27D, termed "molecule details") further comprising a carrier.

[000531] 29D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda um princípio ativo.[000531] 29D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises an active ingredient.

[000532] 30D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, a referida composição compreendendo ainda um princípio ativo selecionado a partir de acaricidas, algicidas, produtos com efeito antialimentar, avicidas, bac- tericidas, repelentes de pássaros, quiomioesterilizantes, fungicidas, fito- protetores contra herbicidas, herbicidas, atrativos de insetos, repelentes de insetos, inseticidas, repelentes de mamíferos, disruptores de acasa-lamento, moluscicidas, nematicidas, ativadores de plantas, reguladores de crescimento de plantas, rodenticidas, sinergistas e virucidas.[000532] 30D. A composition comprising a molecule according to any of the above molecule details, said composition further comprising an active principle selected from acaricides, algaecides, products with anti-food effect, avicides, bactericides, repellents of birds, chemosterilizers, fungicides, phytoprotectants against herbicides, herbicides, insect attractants, insect repellents, insecticides, mammal repellents, mating disruptors, molluscicides, nematicides, plant activators, plant growth regulators, rodenticides, synergists and virucides.

[000533] 31D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda um princípio ativo selecionado de AI- GA.[000533] 31D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises an active principle selected from AIGA.

[000534] 32D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda AI-1.[000534] 32D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises AI-1.

[000535] 33D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda AI-2.[000535] 33D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises AI-2.

[000536] 34D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreendendo ainda Lotilaner.[000536] 34D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprising Lotilaner.

[000537] 35D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda uma molécula selecionada da Tabela A.[000537] 35D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises a molecule selected from Table A.

[000538] 36D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda um princípio ativo selecionado de AI- GA-2.[000538] 36D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises an active ingredient selected from AI-GA-2.

[000539] 37D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda um biopesticida.[000539] 37D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises a biopesticide.

[000540] 38D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda um princípio ativo selecionado de inibidores de Acetilcolinesterase (AChE).[000540] 38D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises an active ingredient selected from Acetylcholinesterase (AChE) inhibitors.

[000541] 39D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo de antagonista de canal de cloro com porta para GABA.[000541] 39D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises a GABA gated chlorine channel antagonist active ingredient.

[000542] 40D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda um princípio ativo de moduladores de canal de sódio.[000542] 40D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises an active principle of sodium channel modulators.

[000543] 41D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo de ago- nistas de receptor nicotínico de acetilcolina (nAChR).[000543] 41D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises an active principle of nicotinic acetylcholine receptor (nAChR) agonists.

[000544] 42D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo de ativa- dores alostéricos de receptor nicotínico de acetilcolina (nAChR).[000544] 42D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises an active principle of allosteric acetylcholine nicotinic receptor (nAChR) activators.

[000545] 43D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda um princípio ativo de ativadores de canal de cloro.[000545] 43D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises an active ingredient of chlorine channel activators.

[000546] 44D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda um princípio ativo selecionado de mímico de hormônio juvenil.[000546] 44D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises an active ingredient selected from juvenile hormone mimic.

[000547] 45D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo de inibidores não específicos gerais (multissítios).[000547] 45D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises an active principle of general non-specific (multisite) inhibitors.

[000548] 46D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda um princípio ativo de Moduladores de Órgãos Cordotonais.[000548] 46D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises an active principle of Cordotonal Organ Modulators.

[000549] 47D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda um princípio ativo de inibidores de crescimento de ácaro.[000549] 47D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises an active principle of mite growth inhibitors.

[000550] 48D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo de disrup- tores microbianos de membranas do intestino médio de insetos.[000550] 48D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises an active principle of microbial disruptors of insect midgut membranes.

[000551] 49D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda um princípio ativo de Inibidores de ATP sintase mitocondrial.[000551] 49D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises an active principle of mitochondrial ATP synthase inhibitors.

[000552] 50D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo de Desa- copladores de fosforilação oxidativa através de disrupção do gradiente de prótons.[000552] 50D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises an active principle of oxidative phosphorylation Decouplers through disruption of the proton gradient.

[000553] 51D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo de blo- queadores de canal de receptor nicotínico de acetilcolina (nA- ChR).[000553] 51D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises an active principle of nicotinic acetylcholine receptor channel blockers (nA-ChR).

[000554] 52D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo de Inibidores de biossíntese de quitina, tipo 0.[000554] 52D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises an active principle of chitin biosynthesis inhibitors, type 0.

[000555] 53D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo de Inibidores de biossíntese de quitina, tipo 1.[000555] 53D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises an active principle of Chitin Biosynthesis Inhibitors, type 1.

[000556] 54D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo de disruptor de ecdise, Dípteros.[000556] 54D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises an ecdysis disruptor active principle, Diptera.

[000557] 55D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo de ago- nistas de receptor de Ecdisona.[000557] 55D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises an Ecdysone receptor agonist active principle.

[000558] 56D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo de ago- nistas de receptor de Octopamina.[000558] 56D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises an active principle of Octopamine receptor agonists.

[000559] 57D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda um princípio ativo de Inibidores de transporte de elétrons do complexo III mitocondrial.[000559] 57D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises an active principle of mitochondrial complex III electron transport inhibitors.

[000560] 58D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda um princípio ativo de Inibidores de transporte de elétrons do complexo I mitocondrial.[000560] 58D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises an active principle of mitochondrial complex I electron transport inhibitors.

[000561] 59D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo de blo- queadores de canais de sódio dependentes de voltagem.[000561] 59D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises an active principle of voltage-dependent sodium channel blockers.

[000562] 60D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes anteriores, em que a referida composição compreende ainda um princípio ativo de Inibidores de acetil CoA carboxilase.[000562] 60D. A composition comprising a molecule according to any of the foregoing details, wherein said composition further comprises an active principle of acetyl CoA carboxylase inhibitors.

[000563] 61D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo de Inibidores de transporte de elétrons do complexo IV mitocondrial.[000563] 61D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises an active principle of mitochondrial complex IV electron transport inhibitors.

[000564] 62D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo de Inibidores de transporte de elétrons do complexo II mitocondrial.[000564] 62D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises an active principle of mitochondrial complex II electron transport inhibitors.

[000565] 63D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo de Modu- ladores de Receptores de Rianodina.[000565] 63D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises an active principle of Rianodine Receptor Modulators.

[000566] 64D.Uma composição compreendendo uma molécula de acordo com qualquer um dos detalhes de molécula anteriores, em que a referida composição compreende ainda um princípio ativo do Grupo UN.[000566] 64D. A composition comprising a molecule according to any of the above molecule details, wherein said composition further comprises an active ingredient from the UN Group.

[000567] 65D.Um processo para controlar uma praga, o referido processo compreendendo a aplicação, a um local, de uma quantidade pesticidamente eficaz de uma molécula, de acordo com qualquer dos detalhes de molécula.[000567] 65D. A process for controlling a pest, said process comprising applying, to a locus, a pesticidally effective amount of a molecule, in accordance with any of the molecule details.

[000568] 66D.Um processo para controlar uma praga, o referido processo compreendendo a aplicação, a um local, de uma quantidade pesticidamente eficaz de uma composição, de acordo com qualquer dos detalhes de 28D a 64D.[000568] 66D. A process for controlling a pest, said process comprising applying, to a locus, a pesticidally effective amount of a composition, in accordance with any of the details 28D to 64D.

[000569] 67D.Um processo de acordo com qualquer um dos detalhes 65D ou 66D, em que a referida praga é selecionada do grupo consistindo em formigas, afídeos, percevejos de cama, besouros, traças, lagartas, baratas, grilos, tesourinhas, pulgas, moscas, gafanhotos, larvas de insetos, cigarrinhas, piolhos, gafanhotos, gafas, ácaros, nemató- deos, fulgoroidea, psilídeos, moscas-serra, cochonilhas, bicho da prata, lesmas, caracóis, aranhas, colêmbolos, marias-fedidas, sínfilos, cupins, tripes, carrapatos, marimbondos, aleirodídeos e salta-martins.[000569] 67D. A process according to any of details 65D or 66D, wherein said pest is selected from the group consisting of ants, aphids, bed bugs, beetles, moths, caterpillars, cockroaches, crickets, earwigs, fleas , flies, locusts, insect larvae, leafhoppers, lice, locusts, gaffes, mites, nematodes, fulgoroidea, psyllids, sawflies, scale insects, silverworm, slugs, snails, spiders, springtails, shinphids, , termites, thrips, ticks, hornets, aleroids and kingfishers.

[000570] 68D.Um processo de acordo com qualquer um dos detalhes 65D ou 66D, onde a referida praga é uma praga que se alimenta de seiva.[000570] 68D. A process according to either detail 65D or 66D, where said pest is a sap-feeding pest.

[000571] 69D.Um processo de acordo com qualquer um dos detalhes 65D ou 66D, em que a referida peste é selecionada do grupo que consiste em afídeos, cigarrinhas, mariposas, cochonilhas-de-escama, tripes, psilídeos, cochonilhas-farinhentas, marias-fedidas e aleirodídeos.[000571] 69D. A process according to any of the details 65D or 66D, wherein said pest is selected from the group consisting of aphids, leafhoppers, moths, scale scale insects, thrips, psyllids, mealy scale insects, Stinky Marys and Aleirodids.

[000572] 70D.Um processo de acordo com qualquer um dos detalhes 65D ou 66D, em que a referida praga é selecionada do grupo consistindo nas Ordens Anoplura e Hemiptera.[000572] 70D. A process according to either detail 65D or 66D, wherein said pest is selected from the group consisting of Orders Anoplura and Hemiptera.

[000573] 71D.Um processo de acordo com qualquer um dos detalhes 65D ou 66D, em que a referida praga é selecionada do grupo consistindo em Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Coccus spp., Euschistus spp., Lygus spp., Macrosiphum spp., Nezara spp. e Rhopalosiphum spp.[000573] 71D. A process according to any one of details 65D or 66D, wherein said pest is selected from the group consisting of Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Coccus spp., Euschistus spp., Lygus spp., Macrosiphum spp., Nezara spp. and Rhopalosiphum spp.

[000574] 72D.Um processo de acordo com qualquer um dos detalhes 65D ou 66D, onde a referida praga é uma praga mastigadora.[000574] 72D. A process according to either detail 65D or 66D, where said pest is a chewing pest.

[000575] 73D.Um processo de acordo com qualquer um dos detalhes 65D ou 66D, em que a referida peste é selecionada do grupo consistindo em lagartas, besouros, gafanhotos e locustas.[000575] 73D. A process according to any one of details 65D or 66D, wherein said pest is selected from the group consisting of caterpillars, beetles, locusts and locusts.

[000576] 74D.Um processo de acordo com qualquer um dos detalhes 65D ou 66D, em que a referida praga é selecionada do grupo consistindo em Coleoptera e Lepidoptera.[000576] 74D. A process according to either detail 65D or 66D, wherein said pest is selected from the group consisting of Coleoptera and Lepidoptera.

[000577] 75D.Um processo de acordo com qualquer um dos detalhes 65D ou 66D em que referida praga é selecionada do grupo consistindo em Anthonomus spp., Cerotoma spp., Chaetocnema spp., Colaspis spp., Cyclocephala spp., Diabrotica spp., Hypera spp., Phyllophaga spp., Phyllotreta spp., Sphenophorus spp., Sitophilus spp.Os títulos no presente documento servem apenas para conveniência e não devem ser utilizados para interpretar qualquer parte do mesmo.

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[000577] 75D. A process according to any one of details 65D or 66D wherein said pest is selected from the group consisting of Anthonomus spp., Cerotoma spp., Chaetocnema spp., Colaspis spp., Cyclocephala spp., Diabrotica spp. , Hypera spp., Phyllophaga spp., Phyllotreta spp., Sphenophorus spp., Sitophilus spp. The headings herein are for convenience only and should not be used to interpret any part thereof.
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Claims (14)

1. Molécula, caracterizada pelo fato de que apresenta a se-guinte fórmula
Figure img0416
na qual(A) R1 é selecionado dentre o grupo consistindo em H, F, Cl, Br e I;(B) R2 é selecionado dentre o grupo consistindo em H, F, Cl, Br, I, CN, (C1-C4)alquila, (C1-C4)alcóxi e (C1-C4)haloalquila;(C) R3 é selecionado dentre o grupo consistindo em H, F, Cl, Br, I, NO2, (C2-C4)alquenila, (C1-C4)alcóxi e (C1-C4)haloalquila;(D) R4 é selecionado dentre o grupo consistindo em H, F, Cl, Br, I, CN, (C1-C4)alquila, (C1-C4)alcóxi e (C1-C4)haloalquila;(E) R5 é selecionado do grupo consistindo em H, F, Cl, Br e I;(F) R6 é selecionado dentre o grupo consistindo em H e (C1-C4) alquila;(G) R7 é selecionado dentre o grupo consistindo em F, Cl, Br e I;(H) R8 é selecionado dentre o grupo consistindo em F, Cl, Br e I;(I) R9 é H;(J) R10 é H;(K) R11 é H;(L) R12 é H; (M) R13 é selecionado dentre o grupo consistindo em H, F, Cl, Br, I e (C1-C4)haloalquila;(N) R14 é H;(O) R15 é selecionado dentre o grupo consistindo em H e (C1-C4)alquila;(P) R16 é selecionado dentre o grupo consistindo em (C3- C8)cicloalquila, azetidinila, isoxazolidinonila, morfolinila, oxazolidinonila, oxetanila, tetra-hidrofuranila, tetra-hidropiranila, tetra-hidrotiofenila, tetra- hidrotiofenil-óxido, tetra-hidrotiofenil-dióxido, e pode ser substituído por um ou mais substituintes selecionados dentre o grupo consistindo em H, F, Cl, Br, I, CN, oxo, (C1-C4)alquila, (C1-C4)haloalquila, C(=O)O(C1-C4)alquila, (C=O)NH(C1-C4)alquila, (C=O)NH(C1-C4) haloalquila, C(=O)(C3-C6)cicloalquila, C(=O)(C1-C4)haloalquila, e (C1-C4)alquil-morfolinila;(Q) Q1 e Q2 são O; eestereoisômeros dissolvidos das moléculas da Fórmula Um.1. Molecule, characterized by the fact that it has the following formula
Figure img0416
in which (A) R1 is selected from the group consisting of H, F, Cl, Br and I; (B) R2 is selected from the group consisting of H, F, Cl, Br, I, CN, (C1-C4 )alkyl, (C1-C4)alkoxy and (C1-C4)haloalkyl; (C) R3 is selected from the group consisting of H, F, Cl, Br, I, NO2, (C2-C4)alkenyl, (C1- C4)alkoxy and (C1-C4)haloalkyl; (D) R4 is selected from the group consisting of H, F, Cl, Br, I, CN, (C1-C4)alkyl, (C1-C4)alkoxy and (C1 -C4)haloalkyl; (E) R5 is selected from the group consisting of H, F, Cl, Br and I; (F) R6 is selected from the group consisting of H and (C1-C4) alkyl; (G) R7 is selected from the group consisting of F, Cl, Br and I;(H) R8 is selected from the group consisting of F, Cl, Br and I;(I) R9 is H;(J) R10 is H;(K) R11 is H; (L) R12 is H; (M) R13 is selected from the group consisting of H, F, Cl, Br, I and (C1-C4)haloalkyl; (N) R14 is H;(O) R15 is selected from the group consisting of H and (C1 -C4)alkyl; (P)R16 is selected from the group consisting of (C3-C8)cycloalkyl, azetidinyl, isoxazolidinonyl, morpholinyl, oxazolidinonyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiophenyloxide , tetrahydrothiophenyldioxide, and may be substituted by one or more substituents selected from the group consisting of H, F, Cl, Br, I, CN, oxo, (C1-C4)alkyl, (C1-C4)haloalkyl, C(=O)O(C1-C4)alkyl, (C=O)NH(C1-C4)alkyl, (C=O)NH(C1-C4) haloalkyl, C(=O)(C3-C6)cycloalkyl , C(=O)(C1-C4)haloalkyl, and (C1-C4)alkyl-morpholinyl; (Q) Q1 and Q2 are O; Dissolved stereoisomers of Formula One molecules. 2. Molécula, de acordo com a reivindicação 1, caracterizada pelo fato de que R1 é selecionado dentre o grupo consistindo em H, F e Cl.2. Molecule according to claim 1, characterized in that R1 is selected from the group consisting of H, F and Cl. 3. Molécula, de acordo com a reivindicação 1, caracterizada pelo fato de que R2 é selecionado dentre o grupo consistindo em H, F, Cl e Br.3. Molecule according to claim 1, characterized in that R2 is selected from the group consisting of H, F, Cl and Br. 4. Molécula, de acordo com a reivindicação 1, caracterizada pelo fato de que R3 é selecionado dentre o grupo consistindo em H, F e Cl.4. Molecule according to claim 1, characterized in that R3 is selected from the group consisting of H, F and Cl. 5. Molécula, de acordo com a reivindicação 1, caracterizada pelo fato de que R4 é selecionado dentre o grupo consistindo em H, F, Cl e Br.5. Molecule according to claim 1, characterized in that R4 is selected from the group consisting of H, F, Cl and Br. 6. Molécula, de acordo com a reivindicação 1, caracterizada pelo fato de que R5 é selecionado dentre o grupo consistindo em H, F e Cl.6. Molecule according to claim 1, characterized in that R5 is selected from the group consisting of H, F and Cl. 7. Molécula, de acordo com a reivindicação 1, caracterizada pelo fato de que R7 e R8 é Cl.7. Molecule according to claim 1, characterized in that R7 and R8 is Cl. 8. Molécula, de acordo com a reivindicação 1, caracterizada pelo fato de que R13 é selecionado dentre o grupo consistindo em H, Cl e CF3.8. Molecule according to claim 1, characterized in that R13 is selected from the group consisting of H, Cl and CF3. 9. Molécula, de acordo com a reivindicação 1, caracterizada pelo fato de que R15 é selecionado dentre o grupo consistindo em H e CH3.9. Molecule according to claim 1, characterized in that R15 is selected from the group consisting of H and CH3. 10. Molécula, de acordo com a reivindicação 1, caracterizada pelo fato de que R16 é selecionado dentre o grupo consistindo em ciclopropila, ciclobutila, ciclopentila, ciclohexila, azetidinila, morfolinila, oxetanila, piranila, tetra-hidrotiofenila, tietanila, tietanil-óxido e tietanil- dióxido,sendo que cada ciclopropila, ciclobutila, ciclopentila, ciclo- hexila, azetidinila, morfolinila, oxetanila, piranila, tetra-hidrotiofenila, tietanila, tietanil-óxido e tietanil-dióxido podem ser opcionalmente substituídos por um ou mais substituintes selecionados do grupo con-sistindo em H, F, CN, C(=O)OC(CH3)3 e C(=O)CF3.10. Molecule according to claim 1, characterized in that R16 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, morpholinyl, oxetanyl, pyranyl, tetrahydrothiophenyl, tiethanyl, tiethanyl-oxide and tiethanyl-dioxide, each of which cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, morpholinyl, oxetanyl, pyranyl, tetrahydrothiophenyl, tietanyl, tiethanyl-oxide and tiethanyl-dioxide may be optionally substituted by one or more substituents selected from the group consisting of H, F, CN, C(=O)OC(CH3)3 and C(=O)CF3. 11. Molécula, de acordo com a reivindicação 1, caracterizada pelo fato de que é selecionado dentre uma das seguintes moléculas:
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11. Molecule according to claim 1, characterized in that it is selected from one of the following molecules:
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 12. Molécula, de acordo com a reivindicação 1, caracterizadapelo fato de que é selecionada dentre as seguintes moléculas:
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12. Molecule according to claim 1, characterized by the fact that it is selected from the following molecules:
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Figure img0443
Figure img0444
 13. Composição, caracterizada pelo fato de que compreende uma molécula, como definida na reivindicação 1, e um ingrediente ativo.13. Composition, characterized in that it comprises a molecule, as defined in claim 1, and an active ingredient. 14. Processo para controlar uma praga, caracterizado pelo fato de que compreende aplicar em um local uma quantidade pestici-damente eficaz de:(a) uma molécula, como definida em qualquer uma das reivindicações de 1 a 12; ou(b) uma composição, como definida na reivindicação 13.14. Process for controlling a pest, characterized in that it comprises applying to a location a pesticidally effective amount of: (a) a molecule, as defined in any one of claims 1 to 12; or (b) a composition as defined in claim 13.
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